Fluoroalkyl-substituted aryltriazole derivatives and uses thereof

ABSTRACT

The present invention relates to novel 5-(fluoroalkyl)-1-aryl-1,2,4-triazole derivatives, to processes for the preparation of such compounds, to pharmaceutical compositions containing such compounds, and to the use of such compounds or compositions for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of renal and cardiovascular diseases.

The present invention relates to novel5-(fluoroalkyl)-1-aryl-1,2,4-triazole derivatives, to processes for thepreparation of such compounds, to pharmaceutical compositions containingsuch compounds, and to the use of such compounds or compositions for thetreatment and/or prevention of diseases, in particular for the treatmentand/or prevention of renal and cardiovascular diseases.

The liquid content of the human body is subject to various physiologicalcontrol mechanisms, the purpose of which is to keep it constant (volumehomeostasis). In the process, both the volume filling of the vascularsystem and also the osmolarity of the plasma are continuously recordedby appropriate sensors (baroreceptors and osmoreceptors). Theinformation which these sensors supply to the relevant centers in thebrain regulates drinking behaviour and controls fluid excretion via thekidneys by means of humoral and neural signals. The peptide hormonevasopressin is of central importance in this [Schrier R. W., Abraham W.T., New Engl. J. Med. 341, 577-585 (1999)].

Vasopressin is produced in specialized endocrine neurons in the Nucleussupraopticus and N. para-ventricularis in the wall of the thirdventricle (hypothalamus) and is transported from there along the neuralprocesses into the posterior lobes of the hypophysis (neurohypophysis).There the hormone is released into the bloodstream in response tostimulus. A loss of volume, e.g. as a result of acute bleeding, heavysweating, prolonged thirst or diarrhoea, is a stimulus for intensifiedrelease of the hormone. Conversely, the secretion of vasopressin isinhibited by an increase in the intravascular volume, e.g. as a resultof increased fluid intake.

Vasopressin exerts its action mainly via binding to three receptors,which are classified as V1a, V1b and V2 receptors and which belong tothe family of G protein-coupled receptors. V1a receptors are mainlylocated on the cells of the vascular smooth musculature. Theiractivation gives rise to vasoconstriction, as a result of which theperipheral resistance and blood pressure rise. Apart from this, V1areceptors are also detectable in the liver. V1b receptors (also named V3receptors) are detectable in the central nervous system. Together withcorticotropin-releasing hormone (CRH), vasopressin regulates the basaland stress-induced secretion of adrenocorticotropic hormone (ACTH) viathe V1b receptor. V2 receptors are located in the distal tubularepithelium and the epithelium of the collecting tubules in the kidney.Their activation renders these epithelia permeable to water. Thisphenomenon is due to the incorporation of aquaporins (special waterchannels) in the luminal membrane of the epithelial cells.

The importance of vasopressin for the reabsorption of water from theurine in the kidney becomes clear from the clinical picture of diabetesinsipidus, which is caused by a deficiency of the hormone, e.g. owing tohypophysis damage. Patients who suffer from this disease excrete up to20 liters of urine per 24 hours if they are not given replacementhormone. This volume corresponds to about 10% of the primary urine.Because of its great importance for the reabsorption of water from theurine, vasopressin is also synonymously referred to as antidiuretichormone (ADH). Consequently, pharmacological inhibition of the action ofvasopressin/ADH on the V2 receptor results in increased urine excretion.In contrast to the action of other diuretics (thiazides and loopdiuretics), however, V2 receptor antagonists cause increased waterexcretion, without substantially increasing the excretion ofelectrolytes. This means that with V2 antagonist drugs, volumehomeostasis can be restored without affecting electrolyte homeostasis.Hence, drugs with V2 antagonistic activity appear particularly suitablefor the treatment of all disease conditions which are associated with anoverloading of the body with water, without the electrolytes beingadequately increased in parallel.

A significant electrolyte abnormality is measurable in clinicalchemistry as hyponatremia (sodium concentration<135 mmol/L); it is themost important electrolyte abnormality in hospital patients, with anincidence of about 5% or 250 000 cases per year in the US alone. If theplasma sodium concentration falls below 115 mmol/L, comatose states anddeath are imminent. Depending on the underlying cause, a distinction ismade between hypovolemic, euvolemic and hypervolemic hyponatremia. Theforms of hypervolemia with edema formation are clinically significant.Typical examples of these are the syndrome of inappropriateADH/vasopressin secretion (SIADH) (e.g. after craniocerebral trauma oras paraneoplasia in carcinomas) and hypervolemic hyponatremia in livercirrhosis, various renal diseases and heart failure [De Luca L. et al.,Am. J. Cardiol. 96 (suppl.), 19 L-23 L (2005)]. In particular, patientswith heart failure, in spite of their relative hyponatremia andhypervolemia, often display elevated vasopressin levels, which are seenas the consequence of a generally disturbed neurohumoral regulation inheart failure [Francis G. S. et al., Circulation 82, 1724-1729 (1990)].

The disturbed neurohormonal regulation essentially manifests itself inan elevation of the sympathetic tone and inappropriate activation of therenin-angiotensin-aldosterone system. While the inhibition of thesecomponents by beta-receptor blockers on the one hand and by ACEinhibitors or angiotensin-receptor blockers on the other is now aninherent part of the pharmacological treatment of heart failure, theinappropriate elevation of vasopressin secretion in advanced heartfailure is at present still not adequately treatable. Apart from theretention of water mediated by V2 receptors and the unfavourablehemodynamic consequences associated therewith in terms of increasedbackload, the emptying of the left ventricle, the pressure in thepulmonary blood vessels and cardiac output are also adversely affectedby V1a-mediated vasoconstriction. Furthermore, on the basis ofexperimental data in animals, a direct hypertrophy-promoting action onthe heart muscle is also attributed to vasopressin. In contrast to therenal effect of volume expansion, which is mediated by activation of V2receptors, the direct action on the heart muscle is triggered byactivation of V1a receptors.

For these reasons, agents which inhibit the action of vasopressin on theV2 and/or the V1a receptor appear suitable for the treatment of heartfailure. In particular, compounds with combined activity on bothvasopressin receptors (V1a and V2) should have both desirable renal aswell as hemodynamic effects and thus offer an especially ideal profilefor the treatment of patients with heart failure. The provision of suchcombined vasopressin antagonists also appears to make sense inasmuch asa volume diminution mediated solely via V2 receptor blockade can entailthe stimulation of osmoreceptors and, as a result, may lead to a furthercompensatory increase in vasopressin release. Through this, in theabsence of a component simultaneously blocking the V1a receptor, theharmful effects of vasopressin, such as for example vasoconstriction andheart muscle hypertrophy, could be further intensified [Saghi P. et al.,Europ. Heart J. 26, 538-543 (2005)].

V1a receptors are mainly located on vascular smooth muscle cells (VSMC)but also on cardiomyocytes, fibroblasts and specialized renal cells likeglomerular mesangial cells or cells of the macula densa which controlthe release of renin [Wasilewski M A, Myers V D, Recchia F A, Feldman AM, Tilley D G, Cell Signal., 28(3), 224-233, (2016)]. The activation ofVSMC V1a receptor by vasopressin gives rise to intracellular calciumrelease and according vasoconstriction. Therefore, stimulation of VSMCV1a receptors causes increased vascular resistance and increased cardiacafterload. Cardiac output is adversely affected by V1a-mediatedvasoconstriction. The increase in afterload and direct stimulation ofV1a receptors on cardiomyocytes can lead to cardiac hypertrophy andremodeling including fibrosis. Mice with cardiac-specific overexpressionof V1a receptor develop cardiac hypertrophy leading to dilation and leftventricular dysfunction, suggesting an essential role for V1a receptorin the development of heart failure [Li X, Chan T O, Myers V, ChowdhuryI, Zhang X Q, Song J, Zhang J, Andrel J, Funakoshi H, Robbins J, Koch WJ, Hyslop T, Cheung J Y, Feldman A M, Circulation.; 124, 572-581(2011)].

V1a receptor is also expressed in the renal cortical and medullaryvasculature, where it mediates vasoconstriction of renal vessels andaffecting overall renal blood flow. Thus, the activation of V1a receptorcan decrease renal medullary blood flow inducing further pathologicalprocesses as tissue hypoxia, reduced oxygen and accordingly energysupply for tubular transport processes as well as direct damages ofmesangial and macula densa cells. It has been demonstrated thatmesangial V1a receptor activation mediates TGFβ signaling and causes anincrease in production of collagen IV. While this signaling contributesextracellular matrix accumulation and remodeling in the kidney, similarsignaling pathways are believed to occur in cardiac cells especiallyafter myocardial infarction, which emphasizes the central role of V1areceptor in the development of hypertrophic and fibrotic processes inresponse to pathophysiological elevated vasopressin levels [Wasilewski MA, Myers V D, Recchia F A, Feldman A M, Tilley D G. Arginine vasopressinreceptor signaling and functional outcomes in heart failure. CellSignal., 28(3), 224-233 (2016)].

Since V1a receptors are mainly expressed on VSMCs and thus participatingin vascular function, a link to vascular diseases as peripheral arterialdisease (PAD) including claudication and critical limb ischemia as wellas coronary microvascular dysfunction (CMD) is conceivable.

Apart from this, V1a receptors are also expressed on human platelets andin the liver. The meaning of platelet V1a receptors is not fullyunderstood although vasopressin induces aggregation of human plateletsvia V1a receptor at high concentrations ex vivo. Therefore, inhibitionof vasopressin-induced platelet aggregation by V1a receptor antagonistsis a useful pharmacological ex vivo assay making use of human tissueendogenously expressing the V1a receptor [Thibonnier M, Roberts J M, JClin Invest.; 76:1857-1864, (1985)].

Vasopressin stimulates gluconeogenesis and glycogenolysis via activationof the hepatic V1a receptor. Animal studies have shown that vasopressinimpairs glucose tolerance which could be inhibited by a V1a receptorantagonist thereby providing a link of vasopressin receptor V1a todiabetes mellitus. [Taveau C, Chollet C, Waeckel L, Desposito D, BichetD G, Arthus M F, Magnan C, Philippe E, Paradis V, Foufelle F, HainaultI, Enhorning S, Velho G, Roussel R, Bankir L, Melander O, Bouby N.Vasopressin and hydration play a major role in the development ofglucose intolerance and hepatic steatosis in obese rats. Diabetologia.,58(5), 1081-1090, (2015)]. Vasopressin was shown to contribute to thedevelopment of albuminuria and to diabetes-induced nephropathy in animalmodels which is consistent with epidemiological findings in humans.

It was found recently that vasopressin also seems to play a causal rolein the development of preeclampsia. Chronic infusion of vasopressinduring pregnancy in mice is sufficient to induce all of the majormaternal and fetal phenotypes associated with human preeclampsia,including pregnancy-specific hypertension [Santillan M K, Santillan D A,Scroggins S M, MM JY, Sandgren J A, Pearson N A, Leslie K K, Hunter S K,Zamba G K, Gibson-Corley K N, Grobe J L. Vasopressin in preeclampsia: anovel very early human pregnancy biomarker and clinically relevant mousemodel. Hypertension. 64(4), 852-859, (2014)].

Vasopressin levels can be elevated in women with dysmenorrhoea (agynecological disorder which is characterised by cyclical crampingpelvic pain) during menstruation, which appear to increase myometrialsmooth muscle contraction. It was found recently that a selectivevasopressin V1a receptor antagonist (relcovaptan/SR-49059) can reduceintrauterine contractions elicited by vasopressin.

For these reasons, agents which inhibit the action of vasopressin on theV1a receptor appear suitable for the treatment of several cardiovasculardiseases. In particular, agents which inhibit the action of vasopressinselectively on the V1a receptor offer an especially ideal profile forthe treatment of otherwise normovolemic patients, i.e. those which arenot eligible for decongestion by e.g. high doses of loop diuretics or V2antagonists, and where induced aquaresis via V2 inhibition may beundesired.

Certain 4-phenyl-1,2,4-triazol-3-yl derivatives have been described inWO 2005/063754-A1 and WO 2005/105779-A1 to act as vasopressin V1areceptor antagonists that are useful for the treatment of gynecologicaldisorders, notably menstrual disorders such as dysmenorrhea.

In WO 2011/104322-A1, a particular group of bis-aryl-bonded1,2,4-triazol-3-ones, including 5-phenyl-1,2,4-triazol-3-yl and1-phenyl-1,2,3-triazol-4-yl derivatives thereof, has been disclosed asantagonists of vasopressin V1a and/or V2 receptors being useful for thetreatment and/or prevention of cardiovascular diseases.

In WO 2016/071212-A1 certain 5-(hydroxyalkyl)-1-phenyl-1,2,4-triazolederivatives have been disclosed, which act as potent antagonists of bothvasopressin V1a and V2 receptors and, in addition, exhibit significantlyenhanced aquaretic potency in vivo after oral application.

It was an object of the present invention to provide novel compoundswhich act as potent selective or dual V1a/V2 receptor antagonists and assuch are suitable for the treatment and/or prevention of diseases, moreparticularly for the treatment and/or prevention of renal andcardiovascular disorders.

The compounds of the present invention have valuable pharmacologicalproperties and can be used for the prevention and/or treatment ofvarious diseases and disease-induced states in humans and other mammals.

In one aspect, the present invention relates to5-(fluoroalkyl)-1-aryl-1,2,4-triazole derivatives of the general formula(I)

in which

-   R¹ represents a trifluoromethyl group    -   or    -   represents a group of the formula —Y—R², wherein    -   Y represents a group of the formula

-   -   -   in which        -   #¹ represents the point of attachment to R²,        -   #² represents the point of attachment to the rest of the            molecule,

    -   R² represents a group selected from a hydrogen atom,        (C₁-C₄)-alkyl, 5- or 6-membered cycloalkyl, 5- or 6-membered        oxaheterocycloalkyl,        -   wherein any (C₁-C₄)-alkyl group and any 5- or 6-membered            cycloalkyl group are each optionally substituted with a            group selected from amino and hydroxy,

-   Ar represents a phenyl group or a 5- or 6-membered heteroaryl group    attached via a ring carbon atom having one or two ring heteroatoms    selected from a nitrogen atom and a sulfur atom,    -   wherein any phenyl group and any 5- or 6-membered heteroaryl        group are each optionally substituted, identically or        differently, with one or two groups selected from a halogen        atom, nitro, cyano, (C₁-C₄)-alkoxy, (C₁-C₄)-alkylsulfanyl,        (C₁-C₄)-alkoxycarbonyl, aminocarbonyl and —S(═O)₂NH₂,        -   wherein said (C₁-C₄)-alkyl group, said (C₁-C₄)-alkoxy group            and said (C₁-C₄)alkylsulfanyl group are each optionally            substituted with up to three fluorine atoms.

The compounds according to this invention can also be present in theform of their salts, solvates and/or solvates of the salts.

The term “substituted” means that one or more hydrogen atoms on thedesignated atom or group are replaced with a selection from theindicated group, provided that the designated atom's normal valencyunder the existing circumstances is not exceeded. Combinations ofsubstituents and/or variables are permissible.

The term “optionally substituted” means that the number of substituentscan be equal to or different from zero. Unless otherwise indicated, itis possible that optionally substituted groups are substituted with asmany optional substituents as can be accommodated by replacing ahydrogen atom with a non-hydrogen substituent on any available carbonatom or heteroatom.

When groups in the compounds according to the invention are substituted,it is possible for said groups to be mono-substituted orpoly-substituted with substituent(s), unless otherwise specified. Withinthe scope of the present invention, the meanings of all groups whichoccur repeatedly are independent from one another. It is possible thatgroups in the compounds according to the invention are substituted withone, two or three identical or different substituents.

The term “comprising” when used in the specification includes“consisting of”.

If within the present text any item is referred to as “as mentionedherein”, it means that it may be mentioned anywhere in the present text.

The terms as mentioned in the present text have the following meanings:

The term “5- to 6-membered heteroaryl” means a monovalent, monocyclicaromatic ring having 5 or 6 ring atoms, which contains at least one ringheteroatom and optionally one, two or three further ring heteroatomsfrom a nitrogen atom and a sulfur atom, and which is bound via a ringcarbon atom or optionally via a ring nitrogen atom (if allowed byvalency).

Said heteroaryl group can be a 5-membered heteroaryl group, such as, forexample, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as,for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl ortriazinyl.

In general, and unless otherwise mentioned, the heteroaryl orheteroarylene groups include all possible isomeric forms thereof, e.g.:tautomers and positional isomers with respect to the point of linkage tothe rest of the molecule. Thus, for some illustrative non-restrictingexamples, the term pyridinyl includes pyridin-2-yl, pyridin-3-yl andpyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.

Particularly, the heteroaryl group in substituent Ar in the generalformula (I), supra, is a pyridinyl group.

The term “halogen atom” means a fluorine, chlorine, bromine or iodineatom, particularly a fluorine, or chlorine atom.

The term “C₁-C₄”, as used in the present text, e.g. in the context ofthe definition of “C₁-C₄-alkyl”, “C₁-C₄-alkoxy”, “or“C₁-C₄-alkylsulfanyl”, means an alkyl group having a finite number ofcarbon atoms of 1 to 4, i.e. 1, 2, 3, or 4 carbon atoms.

The term “C₁-C₄-alkyl” means a linear or branched, saturated, monovalenthydrocarbon group having 1, 2, 3, or 4 carbon atoms, e.g. a methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, or anisomer thereof. Particularly, said group has 1, 2, 3 or 4 carbon atoms(“C₁-C₄-alkyl”), e.g. a methyl, ethyl, propyl, isopropyl, butyl,sec-butyl isobutyl, or tert-butyl group, more particularly 1, 2 or 3carbon atoms (“C₁-C₃-alkyl”), e.g. a methyl, ethyl, n-propyl orisopropyl group, even more particularly a methyl group.

The term “C₁-C₄-alkylsulfanyl” means a linear or branched, saturated,monovalent group of formula (C₁-C₄-alkyl)-S—, in which the term“C₁-C₄-alkyl” is as defined supra, e.g. a methylsulfanyl, ethylsulfanyl,propylsulfanyl, isopropylsulfanyl, butylsulfanyl, sec-butylsulfanyl,isobutylsulfanyl, tert-butylsulfanyl group.

The term “C₁-C₄-alkoxy” means a linear or branched, saturated,monovalent group of formula (C₁-C₄-alkyl)-O—, in which the term“C₁-C₄-alkyl” is as defined supra, e.g. a methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, or an isomerthereof.

It is possible for the compounds of general formula (I) to exist asisotopic variants. The invention therefore includes one or more isotopicvariant(s) of the compounds of general formula (I), particularlydeuterium-containing compounds of general formula (I).

The term “Isotopic variant” of a compound or a reagent is defined as acompound exhibiting an unnatural proportion of one or more of theisotopes that constitute such a compound.

The term “Isotopic variant of the compound of general formula (I)” isdefined as a compound of general formula (I) exhibiting an unnaturalproportion of one or more of the isotopes that constitute such acompound.

The expression “unnatural proportion” means a proportion of such isotopewhich is higher than its natural abundance. The natural abundances ofisotopes to be applied in this context are described in “IsotopicCompositions of the Elements 1997”, Pure Appl. Chem., 70(1), 217-235,1998.

Examples of such isotopes include stable and radioactive isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine,chlorine, bromine and iodine, such as ²H (deuterium), ³H (tritium) ¹¹C,¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S, ¹⁸F, ³⁶Cl, ⁸²Br,¹²³I, ¹²⁴I, ¹²⁵I, ¹²⁹I and ¹³¹I, respectively.

With respect to the treatment and/or prevention of the disordersspecified herein the isotopic variant(s) of the compounds of generalformula (I) preferably contain deuterium (“deuterium-containingcompounds of general formula (I)”). Isotopic variants of the compoundsof general formula (I) in which one or more radioactive isotopes, suchas ³H or ¹⁴C, are incorporated are useful e.g. in drug and/or substratetissue distribution studies. These isotopes are particularly preferredfor the ease of their incorporation and detectability. Positron emittingisotopes such as ¹⁸F or ¹¹C may be incorporated into a compound ofgeneral formula (I). These isotopic variants of the compounds of generalformula (I) are useful for in vivo imaging applications.Deuterium-containing and ¹³C-containing compounds of general formula (I)can be used in mass spectrometry analyses (H. J. Leis et al., Curr. Org.Chem., 1998, 2, 131) in the context of preclinical or clinical studies.

Isotopic variants of the compounds of general formula (I) can generallybe prepared by methods known to a person skilled in the art, such asthose described in the schemes and/or examples herein, by substituting areagent for an isotopic variant of said reagent, preferably for adeuterium-containing reagent. Depending on the desired sites ofdeuteration, in some cases deuterium from D₂O can be incorporated eitherdirectly into the compounds or into reagents that are useful forsynthesizing such compounds (Esaki et al., Tetrahedron, 2006, 62, 10954;Esaki et al., Chem. Eur. J., 2007, 13, 4052). Deuterium gas is also auseful reagent for incorporating deuterium into molecules. Catalyticdeuteration of olefinic bonds (H. J. Leis et al., Curr. Org. Chem.,1998, 2, 131; J. R. Morandi et al., J. Org. Chem., 1969, 34 (6), 1889)and acetylenic bonds (N. H. Khan, J. Am. Chem. Soc., 1952, 74 (12),3018; S. Chandrasekhar et al., Tetrahedron Letters, 2011, 52, 3865) is adirect route for incorporation of deuterium. Metal catalysts (i.e. Pd,Pt, and Rh) in the presence of deuterium gas can be used to directlyexchange deuterium for hydrogen in functional groups containinghydrocarbons (J. G. Atkinson et al., U.S. Pat. No. 3,966,781). A varietyof deuterated reagents and synthetic building blocks are commerciallyavailable from companies such as for example C/D/N Isotopes, Quebec,Canada; Cambridge Isotope Laboratories Inc., Andover, Mass., USA; andCombiPhos Catalysts, Inc., Princeton, N.J., USA. Further information onthe state of the art with respect to deuterium-hydrogen exchange isgiven for example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990;R. P. Hanzlik et al., Biochem. Biophys. Res. Commun. 160, 844, 1989; P.J. Reider et al., J. Org. Chem. 52, 3326-3334, 1987; M. Jarman et al.,Carcinogenesis 16(4), 683-688, 1995; J. Atzrodt et al., Angew. Chem.,Int. Ed. 2007, 46, 7744; K. Matoishi et al., Chem. Commun. 2000,1519-1520; K. Kassahun et al., WO2012/112363.

The term “deuterium-containing compound of general formula (I)” isdefined as a compound of general formula (I), in which one or morehydrogen atom(s) is/are replaced by one or more deuterium atom(s) and inwhich the abundance of deuterium at each deuterated position of thecompound of general formula (I) is higher than the natural abundance ofdeuterium, which is about 0.015%. Particularly, in adeuterium-containing compound of general formula (I) the abundance ofdeuterium at each deuterated position of the compound of general formula(I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferablyhigher than 90%, 95%, 96% or 97%, even more preferably higher than 98%or 99% at said position(s). It is understood that the abundance ofdeuterium at each deuterated position is independent of the abundance ofdeuterium at other deuterated position(s).

The selective incorporation of one or more deuterium atom(s) into acompound of general formula (I) may alter the physicochemical properties(such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc.,2007, 129, 4490; A. Streitwieser et al., J. Am. Chem. Soc., 1963, 85,2759;], basicity [C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127,9641; C. L. Perrin, et al., J. Am. Chem. Soc., 2003, 125, 15008; C. L.Perrin in Advances in Physical Organic Chemistry, 44, 144],lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271])and/or the metabolic profile of the molecule and may result in changesin the ratio of parent compound to metabolites or in the amounts ofmetabolites formed. Such changes may result in certain therapeuticadvantages and hence may be preferred in some circumstances. Reducedrates of metabolism and metabolic switching, where the ratio ofmetabolites is changed, have been reported (A. E. Mutlib et al.,Toxicol. Appl. Pharmacol., 2000, 169, 102; D. J. Kushner et al., Can. J.Physiol. Pharmacol., 1999, 77, 79). These changes in the exposure toparent drug and metabolites can have important consequences with respectto the pharmacodynamics, tolerability and efficacy of adeuterium-containing compound of general formula (I). In some casesdeuterium substitution reduces or eliminates the formation of anundesired or toxic metabolite and enhances the formation of a desiredmetabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol.,2013, 26, 410; Efavirenz: A. E. Mutlib et al., Toxicol. Appl.Pharmacol., 2000, 169, 102). In other cases the major effect ofdeuteration is to reduce the rate of systemic clearance. As a result,the biological half-life of the compound is increased. The potentialclinical benefits would include the ability to maintain similar systemicexposure with decreased peak levels and increased trough levels. Thiscould result in lower side effects and enhanced efficacy, depending onthe particular compound's pharmacokinetic/pharmacodynamic relationship.ML-337 (C. J. Wenthur et al., J. Med. Chem., 2013, 56, 5208) andOdanacatib (K. Kassahun et al., WO2012/112363) are examples for thisdeuterium effect. Still other cases have been reported in which reducedrates of metabolism result in an increase in exposure of the drugwithout changing the rate of systemic clearance (e.g. Rofecoxib: F.Schneider et al., Arzneim. Forsch./Drug. Res., 2006, 56, 295;Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993).Deuterated drugs showing this effect may have reduced dosingrequirements (e.g. lower number of doses or lower dosage to achieve thedesired effect) and/or may produce lower metabolite loads.

A compound of general formula (I) may have multiple potential sites ofattack for metabolism. To optimize the above-described effects onphysicochemical properties and metabolic profile, deuterium-containingcompounds of general formula (I) having a certain pattern of one or moredeuterium-hydrogen exchange(s) can be selected. Particularly, thedeuterium atom(s) of deuterium-containing compound(s) of general formula(I) is/are attached to a carbon atom and/or is/are located at thosepositions of the compound of general formula (I), which are sites ofattack for metabolizing enzymes such as e.g. cytochrome P₄₅₀.

Where the plural form of the word compounds, salts, polymorphs,hydrates, solvates and the like, is used herein, this is taken to meanalso a single compound, salt, polymorph, isomer, hydrate, solvate or thelike.

By “stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The compounds of the present invention optionally contain one asymmetriccentre, depending upon the location and nature of the varioussubstituents desired. It is possible that one asymmetric carbon atom ispresent in the (R) or (S) configuration, which can result in racemicmixtures. In certain instances, it is possible that asymmetry also bepresent due to restricted rotation about a given bond, for example, thecentral bond adjoining two substituted aromatic rings of the specifiedcompounds. Preferred compounds are those which produce the moredesirable biological activity. Separated, pure or partially purifiedisomers and stereoisomers or racemic mixtures of the compounds of thepresent invention are also included within the scope of the presentinvention. The purification and the separation of such materials can beaccomplished by standard techniques known in the art.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, ditoluoyltartaric andcamphorsulfonic acid. Mixtures of diastereoisomers can be separated intotheir individual diastereomers on the basis of their physical and/orchemical differences by methods known in the art, for example, bychromatography or fractional crystallisation. The optically active basesor acids are then liberated from the separated diastereomeric salts. Adifferent process for separation of optical isomers involves the use ofchiral chromatography (e.g., HPLC columns using a chiral phase), with orwithout conventional derivatisation, optimally chosen to maximise theseparation of the enantiomers. Suitable HPLC columns using a chiralphase are commercially available, such as those manufactured by Daicel,e.g., Chiracel OD and Chiracel OJ, for example, among many others, whichare all routinely selectable. Enzymatic separations, with or withoutderivatisation, are also useful. The optically active compounds of thepresent invention can likewise be obtained by chiral syntheses utilizingoptically active starting materials. In order to distinguish differenttypes of isomers from each other reference is made to IUPAC RulesSection E (Pure Appl Chem 45, 11-30, 1976).

The present invention includes all possible stereoisomers of thecompounds of the present invention as single stereoisomers, or as anymixture of said stereoisomers, e.g. (R)- or (S)-isomers, in any ratio.Isolation of a single stereoisomer, e.g. a single enantiomer or a singlediastereomer, of a compound of the present invention is achieved by anysuitable state of the art method, such as chromatography, especiallychiral chromatography, for example.

Further, it is possible for the compounds of the present invention toexist as tautomers. The present invention includes all possibletautomers of the compounds of the present invention as single tautomers,or as any mixture of said tautomers, in any ratio.

Further, the compounds of the present invention can exist as N-oxides,which are defined in that at least one nitrogen of the compounds of thepresent invention is oxidised. The present invention includes all suchpossible N-oxides.

The present invention also covers useful forms of the compounds of thepresent invention, such as metabolites, hydrates, solvates, salts, inparticular pharmaceutically acceptable salts, and/or co-precipitates.

The compounds of the present invention can exist as a hydrate, or as asolvate, wherein the compounds of the present invention contain polarsolvents, in particular water, methanol or ethanol for example, asstructural element of the crystal lattice of the compounds. It ispossible for the amount of polar solvents, in particular water, to existin a stoichiometric or non-stoichiometric ratio. In the case ofstoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-,di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, arepossible. The present invention includes all such hydrates or solvates.Hydrates are preferred solvates in the context of the present invention.

Further, it is possible for the compounds of the present invention toexist in free form, e.g. as a free base, or as a free acid, or as azwitterion, or to exist in the form of a salt. Said salt may be anysalt, either an organic or inorganic addition salt, particularly anypharmaceutically acceptable organic or inorganic addition salt, which iscustomarily used in pharmacy, or which is used, for example, forisolating or purifying the compounds of the present invention.

The term “pharmaceutically acceptable salt” refers to an inorganic ororganic acid addition salt of a compound of the present invention. Forexample, see S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci.1977, 66, 1-19.

A suitable pharmaceutically acceptable salt of the compounds of thepresent invention may be, for example, an acid-addition salt of acompound of the present invention bearing a nitrogen atom, in a chain orin a ring, for example, which is sufficiently basic, such as anacid-addition salt with an inorganic acid, or “mineral acid”, such ashydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric,phosphoric, or nitric acid, for example, or with an organic acid, suchas formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic,butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic,2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic,cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic,pamoic, pectinic, 3-phenylpropionic, pivalic, 2-hydroxyethanesulfonic,itaconic, trifluoromethanesulfonic, dodecylsulfuric, ethanesulfonic,benzenesulfonic, para-toluenesulfonic, methanesulfonic,2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid,citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic,adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic,glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, orthiocyanic acid, for example.

Further, another suitably pharmaceutically acceptable salt of a compoundof the present invention which is sufficiently acidic, is an alkalimetal salt, for example a sodium or potassium salt, an alkaline earthmetal salt, for example a calcium, magnesium or strontium salt, or analuminium or a zinc salt, or an ammonium salt derived from ammonia orfrom an organic primary, secondary or tertiary amine having 1 to 20carbon atoms, such as ethylamine, diethylamine, triethylamine,ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol,diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine,dibenzylamine, N-methylmorpholine, arginine, lysine,1,2-ethylenediamine, N-methylpiperidine, N-methyl-glucamine,N,N-dimethyl-glucamine, N-ethyl-glucamine, 1,6-hexanediamine,glucosamine, sarcosine, serinol, 2-amino-1,3-propanediol,3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol, or a salt with aquarternary ammonium ion having 1 to 20 carbon atoms, such astetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium,tetra(n-butyl) ammonium, N-benzyl-N,N,N-trimethylammonium, choline orbenzalkonium.

Those skilled in the art will further recognise that it is possible foracid addition salts of the claimed compounds to be prepared by reactionof the compounds with the appropriate inorganic or organic acid via anyof a number of known methods. Alternatively, alkali and alkaline earthmetal salts of acidic compounds of the present invention are prepared byreacting the compounds of the present invention with the appropriatebase via a variety of known methods.

The present invention includes all possible salts of the compounds ofthe present invention as single salts, or as any mixture of said salts,in any ratio.

In the present text, in particular in the Experimental Section, for thesynthesis of intermediates and of examples of the present invention,when a compound is mentioned as a salt form with the corresponding baseor acid, the exact stoichiometric composition of said salt form, asobtained by the respective preparation and/or purification process, is,in most cases, unknown.

Unless specified otherwise, suffixes to chemical names or structuralformulae relating to salts, such as “hydrochloride”, “trifluoroacetate”,“sodium salt”, or “x HCl”, “x CF₃COOH”, “x Na⁺” for example, mean a saltform, the stoichiometry of which salt form not being specified.

This applies analogously to cases in which synthesis intermediates orexample compounds or salts thereof have been obtained, by thepreparation and/or purification processes described, as solvates, suchas hydrates, with (if defined) unknown stoichiometric composition.

Furthermore, the present invention includes all possible crystallineforms, or polymorphs, of the compounds of the present invention, eitheras single polymorph, or as a mixture of more than one polymorph, in anyratio.

In a distinct embodiment, the present invention relates to compounds offormula (I), supra, wherein

-   R¹ represents a trifluoromethyl group    -   or    -   represents a group of the formula —Y—R², wherein    -   Y represents a group of the formula

-   -   -   in which        -   #¹ represents the point of attachment to R²,        -   #² represents the point of attachment to the rest of the            molecule,

    -   R² represents a group selected from methyl, aminomethyl,        5-membered cycloalkyl and 4-morpholinyl,        -   wherein any 5-membered cycloalkyl group is optionally            substituted with hydroxy,

-   Ar represents a phenyl group or a pyridine group attached via a ring    carbon atom,    -   wherein any phenyl group any pyridine group is each optionally        substituted with one or two groups selected from a fluorine        atom, a chlorine atom, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, nitro,        cyano, methylsulfanyl and —S(═O)₂NH₂,        -   wherein said (C₁-C₄)-alkyl group and said (C₁-C₄)-alkoxy            group are each optionally substituted with up to three            fluorine atoms,            or a pharmaceutically acceptable salt, hydrate and/or            solvate thereof.

In a preferred embodiment, the present invention relates to compoundsaccording to formula (I), supra, wherein

-   R¹ represents a group of the formula —Y—R², wherein    -   Y represents a group of the formula

-   -   -   in which        -   #¹ represents the point of attachment to R²,        -   #² represents the point of attachment to the rest of the            molecule,

    -   R² represents a methyl group

-   Ar represents a group of the formula

-   -   in which    -   #¹ represents the point of attachment to the nitrogen atom,    -   R^(3A) represents a group selected from cyano and        trifluoromethoxy,

-   R^(3B) represents a group selected from a chlorine atom and    trifluoromethyl,    or a pharmaceutically acceptable salt, hydrate and/or solvate    thereof.

In accordance with a further preferred embodiment, the present inventioncovers compounds of general formula (I), supra, wherein

-   R¹ represents a trifluoromethyl group    -   or    -   represents a group of the formula —Y—R², wherein    -   Y represents a group of the formula

-   -   -   in which        -   #¹ represents the point of attachment to R²,        -   #² represents the point of attachment to the rest of the            molecule,

    -   R² represents a methyl group,

-   Ar represents a group of the formula

-   -   in which    -   #¹ represents the point of attachment to the nitrogen atom,

-   R^(3C) represents a group selected from a fluorine atom and a    chlorine atom,

In accordance with a further preferred embodiment, the present inventioncovers compounds of general formula (I), supra, wherein the compound isselected from the group consisting of

-   5-(4-Chlorophenyl)-2-{[5-(1,1-difluoroethyl)-1-(2-methylphenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;-   5-(4-Chlorophenyl)-2-({1-(2,6-dichlorophenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;-   5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(difluoromethyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;-   5-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-(2-methylphenyl)-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;-   5-(4-Chlorophenyl)-2-({1-(2,6-difluorophenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;-   5-(4-Chlorophenyl)-2-{[5-(1,1-difluoroethyl)-1-(2,6-difluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;-   5-(4-Chlorophenyl)-2-{[1-(2,6-dichlorophenyl)-5-(1,1-difluoroethyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;-   5-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-(2-methylphenyl)-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;-   5-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-[2-(propan-2-yl)phenyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;-   5-(4-Chlorophenyl)-2-({5-(1,1-difluoroethyl)-1-[2-(propan-2-yl)phenyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one-   5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;-   5-(4-Chlorophenyl)-2-({1-(2-ethylphenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;-   5-(4-Chlorophenyl)-2-{[5-(1,1-difluoroethyl)-1-(2-ethylphenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;-   5-(4-Chlorophenyl)-2-({1-[2-(difluoromethoxy)phenyl]-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;-   5-(4-Chlorophenyl)-2-{[5-(1,1-difluoroethyl)-1-(2,6-dimethylphenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;-   5-(4-Chlorophenyl)-2-({5-(1,1-difluoroethyl)-1-[2-(methylsulfanyl)phenyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;    or a pharmaceutically acceptable salt, hydrate and/or solvate    thereof.

In accordance with a further preferred embodiment, the present inventioncovers compounds of general formula (I), supra, wherein

-   R¹ represents a (2S)-3,3,3-trifluoro-2-hydroxypropyl group of the    formula

-   -   in which    -   #¹ represents the point of attachment to the nitrogen atom,        or a pharmaceutically acceptable salt, hydrate and/or solvate        thereof.

-   R¹ represents a (2R)-3,3,3-trifluoro-2-hydroxypropyl group of the    formula

-   -   in which    -   #¹ represents the point of attachment to the nitrogen atom,        or a pharmaceutically acceptable salt, hydrate and/or solvate        thereof.

In a particular further embodiment of the first aspect, the presentinvention covers combinations of two or more of the above mentionedembodiments under the heading “further embodiments of the first aspectof the present invention”.

The present invention covers any sub-combination within any embodimentor aspect of the present invention of compounds of general formula (I),supra.

The present invention covers any sub-combination within any embodimentor aspect of the present invention of intermediate compounds of generalformula (II), (III), (IV), (VI) and (XIV). The present invention coversthe compounds of general formula (I) which are disclosed in the ExampleSection of this text, infra.

In accordance with a second aspect, the present invention covers methodsof preparing compounds of general formula (I) as defined supra, saidmethods comprising the step

[A] of allowing an intermediate compound of formula (II):

-   -   in which    -   R⁴ represents a (C₁-C₄)-alkyl group, in particular a methyl        group,    -   to react in a first step in the presence of an at least        stoichiometric amount of a base with a compound of general        formula (III):

-   -   in which    -   Y and R² are as defined for the compound of general formula (I)        as defined supra,    -   to give an intermediate compound, which is then allowed to react        in a second step with a hydrazine compound of general        formula (IV) or a respective salt thereof

-   -   in which    -   Ar is as defined for the compound of general formula (I) as        defined supra,    -   thereby giving a compound of general formula (I-A):

-   -   in which    -   Y and R² are as defined for the compound of general formula (I)        as defined supra,        or        [B] of allowing an intermediate compound of formula (V):

-   -   to react with a compound of general formula (VI):

-   -   in which    -   R¹ and Ar are as defined for the compound of general formula (I)        as defined supra,    -   thereby giving a compound of general formula (I):

-   -   in which    -   R¹ and Ar are as defined for the compound of general formula (I)        as defined supra,        each [A] and [B] optionally followed, where appropriate, by (i)        separating the compounds of formula (I) thus obtained into their        respective diastereomers, and/or (ii) converting the compounds        of formula (I) into their respective hydrates, solvates, salts        and/or hydrates or solvates of the salts by treatment with the        corresponding solvents and/or acids or bases.

The present invention covers methods of preparing compounds of thepresent invention of general formula (I), said methods comprising thesteps as described in the Experimental Section herein.

The schemes and procedures described below illustrate synthetic routesto the compounds of general formula (I) of the invention and are notintended to be limiting. It is clear to the person skilled in the artthat the order of transformations as exemplified in schemes 1, 2, 3, 4,5, 6, 7 and 8 can be modified in various ways. The order oftransformations exemplified in these schemes is therefore not intendedto be limiting. In addition, interconversion of any of the substituentsR¹, R², R³, R⁴, Y, X and Ar can be achieved before and/or after theexemplified transformations. These modifications can be such as theintroduction of protecting groups, cleavage of protecting groups,reduction or oxidation of functional groups, halogenation, metallation,substitution or other reactions known to the person skilled in the art.These transformations include those which introduce a functionalitywhich allows for further interconversion of substituents. Appropriateprotecting groups and their introduction and cleavage are well-known tothe person skilled in the art (see for example T. W. Greene and P. G. M.Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley1999). Specific examples are described in the subsequent paragraphs.

The multicomponent cyclization [A] is carried out by first reactingimidate of formula (II) with an acid chloride of formula (III) in thepresence of a base to form an intermediate which is in a subsequent stepreacted with the hydrazine compound of formula (IV). Typically theformed intermediate is not isolated and the reaction over the two stepsis performed in one-pot. The hydrazine compound of formula (IV) may alsobe used in form of its salts, such as a hydrochloride salt or a tosylatesalt. Under the alkaline reaction conditions, the hydrazine salt will bereconverted into the free base form. The amount of base added may thenbe adjusted in this respect.

For the preparation of compounds of general formula (I) in which Arconstitutes a pyridine group it may be beneficial in the second step toadd a copper or zinc salt, such as copper(II)sulfate,copper(II)chloride, zinc(II)sulfate and zinc(II)chloride. Typically andpreferably copper(II) sulfate is used.

Suitable bases for both steps are typically tertiary amine bases, suchas N,N-diisopropylethylamine (DIPEA), triethylamine, triisopropylamine,N-methylimidazole, N-methylmorpholine, pyridine and4-(N,N-dimethylamino)pyridine. Preferably, N,N-diisopropylethylamine(DIPEA) is used as base. The reaction is performed in an inert organicsolvent, such as dichloromethane, 1,2-dichloroethane, methyl tert-butylether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene,pyridine, ethyl acetate, acetonitrile or N,N-dimethylformamide, or in amixture of these solvents. Preferably tetrahydrofuran or dioxane or amixture thereof are used as solvents. The first step is generallycarried out at a temperature in the range of −10° C. to +120° C.,preferably at 0° C. The second step is generally carried out at atemperature in the range of +20° C. to +120° C., preferably at roomtemperature. Concomitant microwave irradiation may have a beneficialeffect in this reaction as well at a temperature in the range of +60° C.to +150° C., preferably at +120° C.

The nucleophilic substitution [B] is carried out by first reactingcompound of formula (V) with a compound of formula (VI) in the presenceof base and an optional alkylation catalyst to form a compound ofgeneral formula (I).

Inert solvents for the process step (V)+(VI)→(I) are, for example,halogenated hydrocarbons such as dichloromethane, trichloromethane,carbon tetrachloride, trichloroethylene or chlorobenzene, ethers such asdiethyl ether, diisopropyl ether, methyl tert-butyl ether,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane orbis-(2-methoxyethyl) ether, hydrocarbons such as benzene, toluene,xylene, pentane, hexane, cyclohexane or mineral oil fractions, ordipolar aprotic solvents such as acetone, methyl ethyl ketone, ethylacetate, acetonitrile, N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO),N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (NMP) orpyridine. It is also possible to use mixtures of the solvents mentioned.Preference is given to using tetrahydrofuran, acetonitrile, acetone ordimethylformamide.

Suitable bases for process step (V)+(VI)→(I) are the customary inorganicor organic bases. These preferably include alkali metal hydroxides suchas, for example, lithium hydroxide, sodium hydroxide or potassiumhydroxide, alkali metal or alkaline earth metal carbonates such aslithium carbonate, sodium carbonate, potassium carbonate, calciumcarbonate or cesium carbonate, alkali metal alkoxides such as sodiummethoxide or potassium methoxide, sodium ethoxide or potassium ethoxideor sodium tert-butoxide or potassium tert-butoxide, alkali metalhydrides such as sodium hydride or potassium hydride, amides such assodium amide, lithium bis(trimethylsilyl)amide or potassiumbis(trimethylsilyl)amide or lithium diisopropylamide, or organic aminessuch as triethylamine, N-methylmorpholine, N-methylpiperidine,N,N-diisopropylethylamine, pyridine, 1,5-diazabicyclo[4.3.0]non-5-ene(DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or1,4-diazabicyclo[2.2.2]octane (DABCO®). Preference is given to usingpotassium carbonate or cesium carbonate or sodium hydride.

Here, the base is employed in an amount of from 1 to 5 mol, preferablyin an amount of from 1 to 2.5 mol, based on 1 mole of the compound ofthe formula (V). These process steps may optionally be carried out in anadvantageous manner with addition of alkylation catalysts such as, forexample, lithium bromide, sodium iodide, tetra-n-butylammonium bromideor benzyltriethylammonium chloride. The reactions are generally carriedout in a temperature range of from −20° C. to +150° C., preferably atfrom 0° C. to +80° C. The reactions can be carried out at atmospheric,at elevated or at reduced pressure (for example at from 0.5 to 5 bar);in general, the reactions are carried out at atmospheric pressure.

Compounds of general formula (II) as defined supra, can be prepared by amethod comprising the step

-   [a] of allowing an intermediate compound of formula (V):

-   -   to react with a nitrile compound of general formula (VII):

-   -   in which    -   X represents a leaving group, such as chlorine, bromine, iodine,        mesylate or tosylate, in particular chlorine or bromine,    -   thereby giving a compound of general formula (VIII):

followed by a subsequent step

-   [b] of allowing the compound of general formula (VIII) obtained in    step [a] to react with a basic alcoholate, preferably sodium    methanolate, thereby giving a compound of general formula (II):

-   -   in which    -   R⁴ represents a (C₁-C₄)-alkyl group, in particular a methyl        group.

The N-alkylation reaction (V)+(VII)→(VIII) (step [a]) is typicallycarried out in the presence of a base. Typical and exemplary basesinclude sodium carbonate, potassium carbonate, cesium carbonate,N,N-diisopropylethylamine, triethylamine, sodium tert-butylate orpotassium tert-butylate in acetonitrile, methylisobutylketone, dioxane,dimethylformamide, dimethylacetamide, N-methylpyrrolidinone,dimethylsulfoxide and sulfolane, preference is given to potassiumcarbonate in methylisobutylketone or acetonitrile. The reaction mayoptionally be carried out in an advantageous manner with addition of analkylation catalyst such as, for example, lithium bromide, sodiumiodide, lithium iodide, tetra-n-butylammoniumbromide,tetra-n-butylammoniumiodide or benzyltriethylammoniumchloride. Thereactions are generally carried out in a temperature range of from +40°C. to +120° C., preferably at from +60° C. to +80° C. The reactions canbe carried out at atmospheric, at elevated or at reduced pressure (forexample at from 0.5 to 5 bar); in general, the reactions are carried outat atmospheric pressure. It may be advantageous to slowly perform theaddition of the alkylation agent (VII) over a longer time span.

Conversion to the imidate of general formula (II) can be achieved viastandard reaction protocols known to the person skilled in the art (step[b]: (VIII) (II)). The reaction is typically carried out under basicreactions conditions by reacting with a basic alcoholate. Typical bases,which may be used are sodium methanolate, sodium ethanolate, sodiumpropanolate, sodium isopropoxide, sodium tert-butylate or potassiumtert-butylate in methanol, ethanol, n-propanol, isopropanol, n-butanol,isobutanol and tert-butanol. Preference is given to sodium methanolatein methanol. The reactions are generally carried out in a temperaturerange of from +20° C. to +80° C., preferably at room temperature.

Alternatively, the nitrile compounds of general formula (VIII) mayoptionally also be prepared as shown in the synthetic scheme 1 below:

The amide coupling (IX)→(X) can be carried out directly with the help ofa condensing agent or activating agent in the presence of a base or overtwo steps via an acyl chloride or carboxylic acid imidazolide. Typicalcondensation and activating agents for the amide formation in processsteps (IX)→(X) include, for example, carbodiimides such asN,N′-diethyl-, N, N′-dipropyl-,N,N′-diisopropyl-N,N′-dicyclohexylcarbodiimide (DCC) orN-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC),phosgene derivatives such as N, N′-carbonyldiimidazole (CDI),1,2-oxazolium compounds such as2-ethyl-5-phenyl-1,2-oxazolium-3-sulphate or2-tert-butyl-5-methyl-isoxazolium perchlorate, acylamino compounds suchas 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or isobutylchloroformate, propanephosphonic anhydride, diethyl cyanophosphonate,bis(2-oxo-3-oxazo-lidinyl)phosphoryl chloride,benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate,benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate(PyBOP), O-(benzotriazol-1-yl)-N, N, N′,N′-tetramethyluroniumtetrafluoroborate (TBTU),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(HATU) or O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TCTU), optionally in combination with other additivessuch as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu).The acyl chlorides are typically prepared with thionyl chloride oroxalyl chloride in an inert solvent like dichloromethane orN,N-dimethylformamide. It is also possible to use mixtures of thesolvents mentioned.

Typical and exemplary bases include sodium carbonate, potassiumcarbonate, cesium carbonate, N,N-diisopropylethylamine, triethylamine,sodium tert-butylate or potassium tert-butylate in acetonitrile,methylisobutylketone, dioxane, dimethylformamide, dimethylacetamide,N-methylpyrrolidinone, dimethylsulfoxide and sulfolane, preference isgiven to potassium carbonate in methylisobutylketone or acetonitrile.The reaction may optionally be carried out in an advantageous mannerwith addition of an alkylation catalyst such as, for example, lithiumbromide, sodium iodide, lithium iodide, tetra-n-butylammoniumbromide,tetra-n-butylammoniumiodide or benzyltriethylammoniumchloride. Theconversion to the nitrile (X)→(VIII) can be carried out with the help ofdehydrating agent. Typical dehydrating agents include, for exampletrifluoroacetic acid anhydride, phosphorous pentoxide (P₄O₁₀),phosphoryl chloride (POCl₃), phosphorous pentachloride (PCl₅), CCl₄—PPh₃(Appel reagent), hexamethylphosphoramide (HMPA); methylN-(triethylammoniumsulfonyl)carbamate (Burgess reagent),(Chloromethylene)dimethyliminium chloride (Vilsmeier reagent), oxalylchloride/DMSO and thionylchloride (SOCl₂).

Typical and exemplary solvents for both steps (IX)→(X) and (X)→(VIII)include for example, ethers such as diethyl ether, dioxane,tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethylether, hydrocarbons such as benzene, toluene, xylene, hexane,cyclohexane or mineral oil, fractions, halogenated hydrocarbons such asdichloromethane, trichloromethane, carbon tetrachloride,1,2-dichloroethane, trichloroethylene or chlorobenzene, or othersolvents such as acetone, ethyl acetate, acetonitrile, pyridine,dimethyl sulphoxide, N,N-dimethylformamide, N,N′-dimethylpropyleneurea(DMPU) or N-methylpyrrolidone (NMP). It is also possible to use mixturesof the solvents mentioned.

In a typical and preferred procedure the carboxylic acid (IX) is firstreacted with pivaloyl chloride in the presence of pyridine to form anintermediate which is in a subsequent step reacted with ammonia.Typically the formed intermediate is not isolated and the reaction overthe two steps is performed in one-pot. Suitable as bases for the firststep are preferably, pyridine, 4-(N,N-dimethylamino)pyridine orN,N-diisopropylethylamine (DIPEA). The conversion of carboxamide (X)into nitrile (VIII) is then typically performed by reaction withtrifluoroacetic anhydride. Both reactions are conducted in an inertorganic solvent, preferably tetrahydrofuran.

Compounds of general formula (VI) as defined supra, can be prepared asshown in the synthetic scheme 2 below:

The imidohydrazine formation (IV)+(XI)→(XII) is carried out by firstreacting hydrazine of formula (IV) with an amidine of formula (XI) inthe presence of base to form a compound of general formula (XII).

Typical and exemplary solvents for step (IV)+(XI)→(XII) include polarsolvents, for example, alcohols such as methanol, ethanol, n-propanol,isopropanol, n-butanol or tert-butanol or dipolar aprotic solvents suchas acetonitrile, dioxane, N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO),N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (NMP) orpyridine. Preference is given to using ethanol or tetrahydrofuran.

Suitable bases for process step (IV)+(XI)→(XII) are typically tertiaryamine bases, such as N,N-diisopropylethylamine (DIPEA), triethylamine,triisopropylamine, N-methylimidazole, N-methylmorpholine, pyridine and4-(N,N-dimethylamino)pyridine. Preferably, Triethylamine orN,N-diisopropylethylamine (DIPEA) are used as base. This process step isgenerally carried out at a temperature in the range of −10° C. to +120°C., preferably at 20° C. The reaction can be carried out at atmospheric,at elevated or at reduced pressure (for example at from 0.5 to 5 bar);in general, the reaction is carried out at atmospheric pressure.

The cyclization reaction (XII)+(XIII)→(XIV) is carried out by firstreacting imidohydrazine compounds of general formula (XII) with an acidanhydride compound of formula (XIII) to form a triazole of generalformula (XIV).

Inert solvents for the process step (XII)+(XIII)→(XIV) are, for example,halogenated hydrocarbons such as dichloromethane, trichloromethane,carbon tetrachloride, trichloroethylene or chlorobenzene, ethers such asdiethyl ether, diisopropyl ether, methyl tert-butyl ether,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane orbis-(2-methoxyethyl) ether, hydrocarbons such as benzene, toluene,xylene, pentane, hexane, cyclohexane or mineral oil fractions, ordipolar aprotic solvents such as acetone, methyl ethyl ketone, ethylacetate, acetonitrile, N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO),N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (NMP) orpyridine. It is also possible to use mixtures of the solvents mentioned.Preference is given to using 1,4-dioxane. This process step is generallycarried out at a temperature in the range of −10° C. to +120° C.,preferably at 20° C. The reaction can be carried out at atmospheric, atelevated or at reduced pressure (for example at from 0.5 to 5 bar); ingeneral, the reaction is carried out at atmospheric pressure.

The bromination reaction (XIV)→(VI) is typically carried out with theaid of a halogen source such as N-bromosuccinimide (NBS) and a radicalstarter such as 2,2′-azobis(2-methylpropionitrile) (AIBN) [“Wohl-Zieglerreaction” conditions; see, for instance, A. Wohl, Ber. Dtsch. Chem. Ges.52 (1), 51-63 (1919); K. Ziegler et al., Liebigs. Ann. Chem., 551, 1-79(1942); C. Djerassi, Chem. Rev. 43 (2), 271-317 (1948)].

The compounds of formula (V) and (IX) can be synthesized by theprocedures described in Int. Pat. Appl. WO 2010/105770 and WO2011/104322 (see also synthesis schemes 3 and 4 below).

The compounds of the formula III, IV, VII, XI and XIII are eithercommercially available, known from the literature, or can be preparedfrom readily available starting materials by adaptation of standardmethods described in the literature. Detailed procedures and literaturereferences for preparing the starting materials can also be found in theExperimental Part in the section on the preparation of the startingmaterials and intermediates.

The preparation of the compounds of the invention may be illustrated bymeans of the following synthetic schemes:

The compounds of general formula (I) of the present invention can beconverted to any salt, preferably pharmaceutically acceptable salts, asdescribed herein, by any method which is known to the person skilled inthe art. Similarly, any salt of a compound of general formula (I) of thepresent invention can be converted into the free compound, by any methodwhich is known to the person skilled in the art.

The compounds of the present invention have valuable pharmacologicalproperties and can be used for the prevention and/or treatment ofvarious diseases and disease-induced states in humans and other mammals.Compounds of general formula (I) of the present invention demonstrate avaluable pharmacological spectrum of action and pharmacokinetic profile,both of which could not have been predicted. Compounds of the presentinvention have surprisingly been found to effectively inhibit thevasopressin V1a receptor and it is possible therefore that saidcompounds be used for the treatment and/or prevention of diseases,preferably renal and cardiovascular diseases in humans and animals.

In the context of the present invention, the term “treatment” or“treating” includes inhibiting, delaying, relieving, mitigating,arresting, reducing, or causing the regression of a disease, disorder,condition, or state, the development and/or progression thereof, and/orthe symptoms thereof. The term “prevention” or “preventing” includesreducing the risk of having, contracting, or experiencing a disease,disorder, condition, or state, the development and/or progressionthereof, and/or the symptoms thereof. The term prevention includesprophylaxis. Treatment or prevention of a disorder, disease, condition,or state may be partial or complete.

Throughout this document, for the sake of simplicity, the use ofsingular language is given preference over plural language, but isgenerally meant to include the plural language if not otherwise stated.For example, the expression “A method of treating a disease in apatient, comprising administering to a patient an effective amount of acompound of formula (I)” is meant to include the simultaneous treatmentof more than one disease as well as the administration of more than onecompound of formula (I).

The compounds of the present invention are potent selective or dualantagonists of vasopressin V1a and V2 receptors. The compounds of theinvention are therefore expected to be highly valuable as therapeuticagents for the treatment and/or prevention of diseases, in particularfor the treatment and/or prevention of cardiovascular and renaldiseases.

The compounds according to the invention are suitable for the treatmentand/or prevention of renal diseases, in particular of acute and chronickidney diseases, diabetic kidney diseases, and of acute and chronicrenal failure. The general terms ‘renal disease’ or ‘kidney disease’describe a class of conditions in which the kidneys fail to filter andremove waste products from the blood. There are two major forms ofkidney disease: acute kidney disease (acute kidney injury, AKI) andchronic kidney disease (CKD). The compounds according to the inventionmay further be used for the treatment and/or prevention of sequelae ofacute kidney injury arising from multiple insults such asischemia-reperfusion injury, radiocontrast administration,cardiopulmonary bypass surgery, shock and sepsis. In the sense of thepresent invention, the term renal failure or renal insufficiencycomprises both acute and chronic manifestations of renal insufficiency,as well as underlying or related kidney diseases such as renalhypoperfusion, intradialytic hypotension, obstructive uropathy,glomerulopathies, IgA nephropathy, glomerulonephritis, acuteglomerulonephritis, glomerulosclerosis, tubulointerstitial diseases,nephropathic diseases such as primary and congenital kidney disease,nephritis, Alport syndrome, kidney inflammation, immunological kidneydiseases such as kidney transplant rejection, immune complex-inducedkidney diseases, nephropathy induced by toxic substances, contrastmedium-induced nephropathy; minimal change glomerulonephritis (lipoid);Membranous glomerulonephritis; focal segmental glomerulosclerosis(FSGS); hemolytic uremic syndrome (HUS), amyloidosis, Goodpasture'ssyndrome, Wegener's granulomatosis, Purpura Schönlein-Henoch, diabeticand non-diabetic nephropathy, pyelonephritis, renal cysts,nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome,which can be characterized diagnostically, for example, by abnormallyreduced creatinine and/or water excretion, abnormally increased bloodconcentrations of urea, nitrogen, potassium and/or creatinine, alteredactivity of renal enzymes such as, for example, glutamyl synthetase,altered urine osmolarity or urine volume, increased microalbuminuria,macroalbuminuria, lesions of glomeruli and arterioles, tubulardilatation, hyperphosphataemia and/or the need for dialysis. The presentinvention also comprises the use of the compounds according to theinvention for the treatment and/or prevention of sequelae of renalinsufficiency, for example pulmonary edema, heart failure, uraemia,anaemia, electrolyte disturbances (e.g. hyperkalaemia, hyponatraemia)and disturbances in bone and carbohydrate metabolism. The compoundsaccording to the invention are also suitable for the treatment and/orprevention of polycystic kidney disease (PCKD) and of the syndrome ofinadequate ADH secretion (SIADH).

Cardiovascular diseases in this context that may be treated and/orprevented with the compounds of the invention include, but are notlimited to, the following: acute and chronic heart failure includingworsening chronic heart failure (or hospitalization for heart failure)and including congestive heart failure, arterial hypertension, resistanthypertension, arterial pulmonary hypertension, coronary heart disease,stable and unstable angina pectoris, atrial and ventricular arrhythmias,disturbances of atrial and ventricular rhythm and conductiondisturbances, for example atrioventricular blocks of degree I-III (AVBI-III), supraventricular tachyarrhythmia, atrial fibrillation, atrialflutter, ventricular fibrillation, ventricular flutter, ventriculartachyarrhythmia, torsade-de-pointer tachycardia, atrial and ventricularextrasystoles, AV-junction extrasystoles, sick-sinus syndrome, syncopes,AV-node re-entry tachycardia and Wolff-Parkinson-White syndrome, acutecoronary syndrome (ACS), autoimmune heart diseases (pericarditis,endocarditis, valvulitis, aortitis, cardiomyopathies), shock such ascardiogenic shock, septic shock and anaphylactic shock, aneurysms, Boxercardiomyopathy (premature ventricular contraction), furthermorethromboembolic diseases and ischaemias such as peripheral perfusiondisturbances, reperfusion injury, arterial and venous thromboses,myocardial insufficiency, endothelial dysfunction, micro- andmacrovascular damage (vasculitis) and for preventing restenoses such asafter thrombolysis therapies, percutaneous transluminal angioplasty(PTA), percutaneous transluminal coronary angioplasty (PTCA), hearttransplantation and bypass operations, arteriosclerosis, disturbances oflipid metabolism, hypolipoproteinaemias, dyslipidemias,hypertriglyceridemias, hyperlipidemias and combined hyperlipidemias,hypercholesterolaemias, abetalipoproteinaemia, sitosterolemia,xanthomatosis, Tangier disease, adipositas, obesity, metabolic syndrome,transitory and ischemic attacks, stroke, inflammatory cardiovasculardiseases, peripheral and cardiac vascular diseases, peripheralcirculation disorders, spasms of the coronary arteries and peripheralarteries, and edema such as, for example, pulmonary edema, cerebraledema, renal edema and heart failure-related edema.

In the sense of the present invention, the term heart failure alsoincludes more specific or related disease forms such as right heartfailure, left heart failure, global insufficiency, ischemiccardiomyopathy, dilatative cardiomyopathy, congenital heart defects,heart valve defects, heart failure with heart valve defects, mitralvalve stenosis, mitral valve insufficiency, aortic valve stenosis,aortic valve insufficiency, tricuspidal stenosis, tricuspidalinsufficiency, pulmonary valve stenosis, pulmonary valve insufficiency,combined heart valve defects, heart muscle inflammation (myocarditis),chronic myocarditis, acute myocarditis, viral myocarditis, diabeticheart failure, alcohol-toxic cardiomyopathy, cardiac storage diseases,heart failure with preserved ejection fraction (HFpEF or diastolic heartfailure), and heart failure with reduced ejection fraction (HFrEF orsystolic heart failure).

The compounds according to the invention are also suitable for thetreatment and/or prevention of renal diseases, in particular of acuteand chronic renal insufficiency, and of acute and chronic renal failure.In the sense of the present invention, the term renal insufficiencycomprises both acute and chronic manifestations of renal insufficiency,as well as underlying or related kidney diseases such as renalhypoperfusion, intradialytic hypotension, obstructive uropathy,glomerulopathies, IgA nephropathy, glomerulonephritis, acuteglomerulonephritis, glomerulosclerosis, tubulointerstitial diseases,nephropathic diseases such as primary and congenital kidney disease,nephritis, immunological kidney diseases such as kidney transplantrejection, immune complex-induced kidney diseases, nephropathy inducedby toxic substances, contrast medium-induced nephropathy, diabetic andnon-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis,hypertensive nephrosclerosis and nephrotic syndrome, which can becharacterized diagnostically, for example, by abnormally reducedcreatinine and/or water excretion, abnormally increased bloodconcentrations of urea, nitrogen, potassium and/or creatinine, alteredactivity of renal enzymes such as, for example, glutamyl synthetase,altered urine osmolarity or urine volume, increased microalbuminuria,macroalbuminuria, lesions of glomeruli and arterioles, tubulardilatation, hyperphosphataemia and/or the need for dialysis. The presentinvention also comprises the use of the compounds according to theinvention for the treatment and/or prevention of sequelae of renalinsufficiency, for example pulmonary edema, heart failure, uraemia,anaemia, electrolyte disturbances (e.g. hyperkalaemia, hyponatraemia)and disturbances in bone and carbohydrate metabolism.

The compounds of the present invention may be particularly useful forthe treatment and/or prevention of the cardiorenal syndrome (CRS) andits various subtypes. This term embraces certain disorders of the heartand kidneys whereby acute or chronic dysfunction in one organ may induceacute or chronic dysfunction of the other. CRS has been sub-classifiedinto five types based upon the organ that initiated the insult as wellas the acuity and chronicity of the disease (type 1: development ofrenal insufficiency resulting from acute decompensated heart failure;type 2: chronic congestive heart failure resulting in progressive renaldysfunction; type 3: acute cardiac dysfunction resulting from an abruptfall in renal function; type 4: chronic kidney disease leading tocardiac remodeling; type 5: systemic disease involving both the heartand the kidneys) [see, for example, M. R. Kahn et al., Nature Rev.Cardiol. 10, 261-273 (2013)].

The compounds according to the invention are also suitable for thetreatment and/or prevention of polycystic kidney disease (PCKD) and ofthe syndrome of inadequate ADH secretion (SIADH). Furthermore, thecompounds of the invention are suitable for use as a diuretic for thetreatment of edemas and in electrolyte disorders, in particular inhypervolemic and euvolemic hyponatremia.

Moreover, the compounds according to the invention may be used for thetreatment and/or prevention of peripheral arterial disease (PAD)including claudication and including critical limb ischemia coronarymicrovascular dysfunction (CMD) including CMD type 1-4, primary andsecondary Raynaud's phenomenon, microcirculation disturbances,claudication, peripheral and autonomic neuropathies, diabeticmicroangiopathies, diabetic retinopathy, diabetic limb ulcers, gangrene,CREST syndrome, erythematous disorders, onychomycosis, rheumaticdiseases and for promoting wound healing.

Furthermore, the compounds of the invention are suitable for treatingurological diseases and diseases of the male and female urogenitalsystem such as, for example, benign prostatic syndrome (BPS), benignprostatic hyperplasia (BPH), benign prostatic enlargement (BPE), bladderoutlet obstruction (BOO), lower urinary tract syndromes (LUTS),neurogenic overactive bladder (OAB), interstitial cystitis (IC), urinaryincontinence (UI) such as, for example, mixed, urge, stress and overflowincontinence (MUI, UUI, SUI, OUI), pelvic pains, erectile dysfunction,dysmenorrhea and endometriosis.

The compounds according to the invention may also be used for thetreatment and/or prevention of inflammatory diseases, asthmaticdiseases, chronic obstructive pulmonary disease (COPD), acuterespiratory distress syndrome (ARDS), acute lung injury (ALI),alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonaryemphysema (e.g. smoking-induced pulmonary emphysema) and cystic fibrosis(CF). In addition, the compounds of the invention may be used for thetreatment and/or prevention of pulmonary arterial hypertension (PAH) andother forms of pulmonary hypertension (PH), including pulmonaryhypertension associated with left ventricular disease, HIV infection,sickle cell anaemia, thromboembolism (CTEPH), sarcoidosis, chronicobstructive pulmonary disease (COPD) or pulmonary fibrosis.

Additionally, the compounds according to the invention may be used forthe treatment and/or prevention of liver cirrhosis, ascites, diabetesmellitus and diabetic complications such as, for example, neuropathy andnephropathy.

Further, the compounds of the invention are suitable for the treatmentand/or prevention of central nervous disorders such as anxiety states,depression, glaucoma, cancer such as in particular pulmonary tumors, andcircadian rhythm misalignment such as jet lag and shift work.

Furthermore, the compounds according to the invention may be useful forthe treatment and/or prevention of pain conditions, diseases of theadrenals such as, for example, pheochromocytoma and adrenal apoplexy,diseases of the intestine such as, for example, Crohn's disease anddiarrhea, menstrual disorders such as, for example, dysmenorrhea,endometriosis, preterm labor and tocolysis.

Due to their activity and selectivity profile, the compounds of thepresent invention are believed to be particularly suitable for thetreatment and/or prevention of acute and chronic kidney diseasesincluding diabetic nephropathy, acute and chronic heart failure,preeclampsia, peripheral arterial disease (PAD), coronary microvasculardysfunction (CMD), Raynaud's syndrome, dysmenorrhea, cardiorenalsyndrome, hypervolemic and euvolemic hyponatremia, liver cirrhosis,ascites, edema and the syndrome of inadequate ADH secretion (SIADH).

The diseases mentioned above have been well characterized in humans, butalso exist with a comparable etiology in other mammals, and may betreated in those with the compounds and methods of the presentinvention.

Thus, the present invention further relates to the use of the compoundsaccording to the invention for the treatment and/or prevention ofdiseases, especially of the aforementioned diseases.

The present invention further relates to the use of the compoundsaccording to the invention for preparing a pharmaceutical compositionfor the treatment and/or prevention of diseases, especially of theaforementioned diseases.

The present invention further relates to the use of the compoundsaccording to the invention in a method for the treatment and/orprevention of diseases, especially of the aforementioned diseases.

The present invention further relates to a method for the treatmentand/or prevention of diseases, especially of the aforementioneddiseases, by using an effective amount of at least one of the compoundsaccording to the invention.

In accordance with another aspect, the present invention coverspharmaceutical combinations, in particular medicaments, comprising atleast one compound of general formula (I) of the present invention andat least one or more further active ingredients, in particular for thetreatment and/or prevention of diseases, especially of theaforementioned diseases.

Particularly, the present invention covers a pharmaceutical combination,which comprises:

-   -   one or more first active ingredients, in particular compounds of        general formula (I) as defined supra, and    -   one or more further active ingredients, in particular for the        treatment and/or prevention of diseases, especially of the        aforementioned diseases.

The term “combination” in the present invention is used as known topersons skilled in the art, it being possible for said combination to bea fixed combination, a non-fixed combination or a kit-of-parts.

A “fixed combination” in the present invention is used as known topersons skilled in the art and is defined as a combination wherein, forexample, a first active ingredient, such as one or more compounds ofgeneral formula (I) of the present invention, and a further activeingredient are present together in one unit dosage or in one singleentity. One example of a “fixed combination” is a pharmaceuticalcomposition wherein a first active ingredient and a further activeingredient are present in admixture for simultaneous administration,such as in a formulation. Another example of a “fixed combination” is apharmaceutical combination wherein a first active ingredient and afurther active ingredient are present in one unit without being inadmixture.

A non-fixed combination or “kit-of-parts” in the present invention isused as known to persons skilled in the art and is defined as acombination wherein a first active ingredient and a further activeingredient are present in more than one unit. One example of a non-fixedcombination or kit-of-parts is a combination wherein the first activeingredient and the further active ingredient are present separately. Itis possible for the components of the non-fixed combination orkit-of-parts to be administered separately, sequentially,simultaneously, concurrently or chronologically staggered.

The compounds of the present invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutically active ingredients where the combination causes nounacceptable adverse effects. The present invention also covers suchpharmaceutical combinations. For example, the compounds of the presentinvention can be combined with known agents for the treatment and/orprevention of diseases, especially of the aforementioned diseases.

In particular, the compounds of the present invention may be used infixed or separate combination with

-   -   antithrombotic agents, for example and preferably from the group        of platelet aggregation inhibitors, anticoagulants and        profibrinolytic substances;    -   blood pressure lowering agents, for example and preferably from        the group of calcium antagonists, angiotensin AII antagonists,        ACE inhibitors, NEP inhibitors, vasopeptidase inhibitors,        endothelin antagonists, renin inhibitors, alpha-blockers,        beta-blockers, mineralocorticoid receptor antagonists and        diuretics;    -   antidiabetic agents (hypoglycemic or antihyperglycemic agents),        such as for example and preferably insulin and derivatives,        sulfonylureas, biguanides, thiazolidinediones, acarbose, DPP4        inhibitors, GLP-1 analogues, or SGLT inhibitors (gliflozins).    -   organic nitrates and NO-donors, for example sodium        nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide        dinitrate, molsidomine or SIN-1, and inhalational NO;        -   compounds that inhibit the degradation of cyclic guanosine            monophosphate (cGMP), for example inhibitors of            phosphodiesterases (PDE) 1, 2, 5 and/or 9, in particular            PDE-5 inhibitors such as sildenafil, vardenafil, tadalafil,            udenafil, dasantafil, avanafil, mirodenafil, lodenafil,            CTP-499 or PF-00489791;    -   positive-inotropic agents, such as for example cardiac        glycosides (digoxin) and beta-adrenergic and dopaminergic        agonists such as isoproterenol, adrenalin, noradrenalin,        dopamine or dobutamine;    -   natriuretic peptides, such as for example atrial natriuretic        peptide (ANP, anaritide), B-type natriuretic peptide or brain        natriuretic peptide (BNP, nesiritide), C-type natriuretic        peptide (CNP) or urodilatin;    -   calcium sensitizers, such as for example and preferably        levosimendan;    -   NO- and heme-independent activators of soluble guanylate cyclase        (sGC for example and with preference the compounds described in        WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462        and WO 02/070510;    -   NO-independent, but heme-dependent stimulators of guanylate        cyclase (sGC), for example and with preference the compounds        described in WO 00/06568, WO 00/06569, WO 02/42301, WO        03/095451, WO 2011/147809, WO 2012/004258, WO 2012/028647 and WO        2012/059549;    -   agents, that stimulates the synthesis of cGMP, for example and        with preference sGC modulators, for example and with preference        riociguat, cinaciguat, vericiguat or BAY 1101042;    -   inhibitors of human neutrophil elastase (HNE), such as for        example sivelestat or DX-890 (reltran);    -   compounds inhibiting the signal transduction cascade, in        particular tyrosine and/or serine/threonine kinase inhibitors,        such as for example nintedanib, dasatinib, nilotinib, bosutinib,        regorafenib, sorafenib, sunitinib, cediranib, axitinib,        telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib,        erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib,        semaxanib or tandutinib;        -   compounds influencing the energy metabolism of the heart,            such as for example and preferably etomoxir,            dichloroacetate, ranolazine or trimetazidine, or full or            partial adenosine A1 receptor agonists as GS-9667            (previously known as CVT-3619), capadenoson and neladenoson            and (BAY 1067197)    -   compounds influencing the heart rate, such as for example and        preferably ivabradine;    -   cardiac myosin activators, such as for example and preferably        omecamtiv mecarbil (CK-1827452);        -   anti-inflammatory drugs such as non-steroidal            anti-inflammatory drugs (NSAIDs) including acetylsalicylic            acid (aspirin), ibuprofen and naproxen, glucocorticoids, NEP            inhibitors, 5-aminosalicylic acid derivatives, leukotriene            antagonists, TNF-alpha inhibitors and chemokine receptor            antagonists such as CCR1, 2 and/or 5 inhibitors;    -   fat metabolism altering agents, for example and preferably from        the group of thyroid receptor agonists, cholesterol synthesis        inhibitors, such as for example and preferably HMG-CoA-reductase        or squalene synthesis inhibitors, ACAT inhibitors, CETP        inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or        PPAR-delta agonists, cholesterol absorption inhibitors, lipase        inhibitors, polymeric bile acid adsorbers, bile acid        reabsorption inhibitors and lipoprotein(a) antagonists.

Antithrombotic agents are preferably to be understood as compounds fromthe group of platelet aggregation inhibitors, anticoagulants andprofibrinolytic substances.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a plateletaggregation inhibitor, for example and preferably aspirin, clopidogrel,ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thrombin inhibitor,for example and preferably ximelagatran, dabigatran, melagatran,bivalirudin or enoxaparin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a GPIIb/IIIaantagonist, for example and preferably tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a factor Xainhibitor, for example and preferably rivaroxaban, apixaban, otamixaban,fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112,YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with heparin or a lowmolecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a vitamin Kantagonist, for example and preferably coumarin.

Blood pressure lowering agents are preferably to be understood ascompounds from the group of calcium antagonists, angiotensin AIIantagonists, ACE inhibitors, NEP inhibitors, vasopeptidase inhibitors,endothelin antagonists, renin inhibitors, alpha-blockers, beta-blockers,mineralocorticoid receptor antagonists and diuretics.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a calcium antagonist,for example and preferably nifedipine, amlodipine, verapamil ordiltiazem.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an alpha-1-receptorblocker, for example and preferably prazosin or tamsulosin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a beta-blocker, forexample and preferably propranolol, atenolol, timolol, pindolol,alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol,mepindolol, carazolol, sotalol, metoprolol, betaxolol, celiprolol,bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol,landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an angiotensin AIIreceptor antagonist, for example and preferably losartan, candesartan,valsartan, telmisartan, irbesartan, olmesartan, eprosartan, embursartanor azilsartan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a vasopeptidaseinhibitor or inhibitor of neutral endopeptidase (NEP), such as forexample and preferably sacubitril, omapatrilat or AVE-7688.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a dual angiotensinAII receptor antagonist/NEP inhibitor (ARNI), for example and preferablyLCZ696.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACE inhibitor, forexample and preferably enalapril, captopril, lisinopril, ramipril,delapril, fosinopril, quinopril, perindopril, benazepril or trandopril.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an endothelinantagonist, for example and preferably bosentan, darusentan,ambrisentan, tezosentan, sitaxsentan, avosentan, macitentan oratrasentan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a renin inhibitor,for example and preferably aliskiren, SPP-600 or SPP800.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a mineralocorticoidreceptor antagonist, for example and preferably finerenone,spironolactone, canrenone, potassium canrenoate, eplerenone, esaxerenone(CS-3150), or apararenone (MT-3995), CS-3150, or MT-3995.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a diuretic, such asfor example and preferably furosemide, bumetanide, piretanide,torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide,xipamide, indapamide, hydroflumethiazide, methyclothiazide,polythiazide, trichloromethiazide, chlorothalidone, metolazone,quinethazone, acetazolamide, dichlorophenamide, methazolamide,glycerine, isosorbide, mannitol, amiloride or triamterene.

Fat metabolism altering agents are preferably to be understood ascompounds from the group of CETP inhibitors, thyroid receptor agonists,cholesterol synthesis inhibitors such as HMG-CoA-reductase or squalenesynthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha,PPAR-gamma and/or PPAR-delta agonists, cholesterol absorptioninhibitors, polymeric bile acid adsorbers, bile acid reabsorptioninhibitors, lipase inhibitors and lipoprotein(a) antagonists.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a CETP inhibitor, forexample and preferably dalcetrapib, anacetrapib, BAY 60-5521 orCETP-vaccine (Avant).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thyroid receptoragonist, for example and preferably D-thyroxin, 3,5,3′-triiodothyronin(T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an HMG-CoA-reductaseinhibitor from the class of statins, for example and preferablylovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin,rosuvastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a squalene synthesisinhibitor, for example and preferably BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACAT inhibitor,for example and preferably avasimibe, melinamide, pactimibe, eflucimibeor SMP-797.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an MTP inhibitor, forexample and preferably implitapide, R-103757, BMS-201038 or ITT-130.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-gamma agonist,for example and preferably pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-delta agonist,for example and preferably GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a cholesterolabsorption inhibitor, for example and preferably ezetimibe, tiqueside orpamaqueside.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipase inhibitor,for example and preferably orlistat.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a polymeric bile acidadsorber, for example and preferably cholestyramine, colestipol,colesolvam, CholestaGel or colestimide.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a bile acidreabsorption inhibitor, for example and preferably ASBT (=IBAT)inhibitors such as AZD-7806, S-8921, AK-105, BARI-1741, SC-435 orSC-635.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipoprotein(a)antagonist, for example and preferably gemcabene calcium (CI-1027) ornicotinic acid.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a TGFbeta antagonist,by way of example and with preference pirfenidone or fresolimumab.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with HIF-PH inhibitors, byway of example and with preference molidustat or roxadustat.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a CCR2 antagonist, byway of example and with preference CCX-140.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a TNFalphaantagonist, by way of example and with preference adalimumab.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a galectin-3inhibitor, by way of example and with preference GCS-100.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a BMP-7 agonist, byway of example and with preference THR-184.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a NOX1/4 inhibitor,by way of example and with preference GKT-137831.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a medicament whichaffects the vitamin D metabolism, by way of example and with preferencecholecalciferol or paracalcitol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a cytostatic agent,by way of example and with preference cyclophosphamide.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an immunosuppressiveagent, by way of example and with preference ciclosporin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a phosphate binder,by way of example and with preference sevelamer or lanthanum carbonate.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a calcimimetic fortherapy of hyperparathyroidism.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with agents for irondeficit therapy, by way of example and with preference iron products.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with agents for thetherapy of hyperurikaemia, by way of example and with preferenceallopurinol or rasburicase.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with glycoprotein hormonefor the therapy of anaemia, by way of example and with preferenceerythropoietin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with biologics for immunetherapy, by way of example and with preference abatacept, rituximab,eculizumab or belimumab.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with Jak inhibitors, byway of example and with preference ruxolitinib, tofacitinib,baricitinib, CYT387, GSK2586184, lestaurtinib, pacritinib (SB1518) orTG101348.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with prostacyclin analogsfor therapy of microthrombi.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an alkali therapy, byway of example and with preference sodium bicarbonate.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an mTOR inhibitor, byway of example and with preference everolimus or rapamycin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an NHE3 inhibitor, byway of example and with preference AZD1722.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an eNOS modulator, byway of example and with preference sapropterin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a CTGF inhibitor, byway of example and with preference FG-3019.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with antidiabetics(hypoglycemic or antihyperglycemic agents), such as for example andpreferably insulin and derivatives, sulfonylureas such as tolbutamide,carbutamide, acetohexamide, chlorpropamide, glipizide, gliclazide,glibenclamide, glyburide, glibornuride, gliquidone, glisoxepide,glyclopyramide, glimepiride, JB253 and JB558, meglitinides such asrepaglinide and nateglinide, biguanides such as metformin and buformin,thiazolidinediones such as rosiglitazone and pioglitazone,alpha-glucosidase inhibitors such as miglitol, acarbose and voglibose,DPP4 inhibitors such as vildagliptin, sitagliptin, saxagliptin,linagliptin, alogliptin, septagliptin and teneligliptin, GLP-1 analoguessuch as exenatide (also exendin-4, liraglutide, lixisenatide andtaspoglutide, or SGLT inhibitors (gliflozins) such as canagliflozin,dapagliflozin and empagliflozin.

In a particularly preferred embodiment, the compounds of the presentinvention are administered in combination with one or more additionaltherapeutic agents selected from the group consisting of diuretics,angiotensin AII antagonists, ACE inhibitors, beta-receptor blockers,mineralocorticoid receptor antagonists, antidiabetics, organic nitratesand NO donors, activators and stimulators of the soluble guanylatecyclase (sGC), and positive-inotropic agents.

In a further particularly preferred embodiment, the compounds of thepresent invention are administered in combination with one or moreadditional therapeutic agents selected from the group consisting ofdiuretics, angiotensin AII antagonists, ACE inhibitors, beta-receptorblockers, mineralocorticoid receptor antagonists, antidiabetics, organicnitrates and NO donors, activators and stimulators of the solubleguanylate cyclase (sGC), positive-inotropic agents, antiinflammatoryagents, immunosuppressive agents, phosphate binders and/or compoundswhich modulate vitamin D metabolism.

Thus, in a further embodiment, the present invention relates topharmaceutical compositions comprising at least one of the compoundsaccording to the invention and one or more additional therapeutic agentsfor the treatment and/or prevention of diseases, especially of theaforementioned diseases.

Furthermore, the compounds of the present invention may be utilized, assuch or in compositions, in research and diagnostics, or as analyticalreference standards and the like, which are well known in the art.

When the compounds of the present invention are administered aspharmaceuticals, to humans and other mammals, they can be given per seor as a pharmaceutical composition containing, for example, 0.1% to99.5% (more preferably, 0.5% to 90%) of active ingredient in combinationwith one or more pharmaceutically acceptable excipients.

Thus, in another aspect, the present invention relates to pharmaceuticalcompositions comprising at least one of the compounds according to theinvention, conventionally together with one or more inert, non-toxic,pharmaceutically acceptable excipients, and to the use thereof for thetreatment and/or prevention of diseases, especially of theaforementioned diseases.

It is possible for the compounds according to the invention to havesystemic and/or local activity. For this purpose, they can beadministered in a suitable manner, such as, for example, via the oral,parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal,vaginal, dermal, transdermal, conjunctival, otic route or as an implantor stent.

For these administration routes, it is possible for the compoundsaccording to the invention to be administered in suitable administrationforms.

For oral administration, it is possible to formulate the compoundsaccording to the invention to dosage forms known in the art that deliverthe compounds of the invention rapidly and/or in a modified manner, suchas, for example, tablets (uncoated or coated tablets, for example withenteric or controlled release coatings that dissolve with a delay or areinsoluble), orally-disintegrating tablets, films/wafers,films/lyophylisates, capsules (for example hard or soft gelatinecapsules), sugar-coated tablets, granules, pellets, powders, emulsions,suspensions, aerosols or solutions. It is possible to incorporate thecompounds according to the invention in crystalline and/or amorphisedand/or dissolved form into said dosage forms.

Parenteral administration can be effected with avoidance of anabsorption step (for example intravenous, intraarterial, intracardial,intraspinal or intralumbal) or with inclusion of absorption (for exampleintramuscular, subcutaneous, intracutaneous, percutaneous orintraperitoneal). Administration forms which are suitable for parenteraladministration are, inter alia, preparations for injection and infusionin the form of solutions, suspensions, emulsions, lyophylisates orsterile powders.

Examples which are suitable for other administration routes arepharmaceutical forms for inhalation [inter alia powder inhalers,nebulizers], nasal drops, nasal solutions, nasal sprays;tablets/films/wafers/capsules for lingual, sublingual or buccaladministration; suppositories; eye drops, eye ointments, eye baths,ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, eartampons; vaginal capsules, aqueous suspensions (lotions, mixturaeagitandae), lipophilic suspensions, emulsions, ointments, creams,transdermal therapeutic systems (such as, for example, patches), milk,pastes, foams, dusting powders, implants or stents.

The compounds according to the invention can be incorporated into thestated administration forms. This can be effected in a manner known perse by mixing with pharmaceutically suitable excipients. Pharmaceuticallysuitable excipients include, inter alia,

-   -   fillers and carriers (for example cellulose, microcrystalline        cellulose (such as, for example, Avicel®), lactose, mannitol,        starch, calcium phosphate (such as, for example, Di-Cafos®)),    -   ointment bases (for example petroleum jelly, paraffins,        triglycerides, waxes, wool wax, wool wax alcohols, lanolin,        hydrophilic ointment, polyethylene glycols),    -   bases for suppositories (for example polyethylene glycols, cacao        butter, hard fat),    -   solvents (for example water, ethanol, isopropanol, glycerol,        propylene glycol, medium chain-length triglycerides fatty oils,        liquid polyethylene glycols, paraffins),    -   surfactants, emulsifiers, dispersants or wetters (for example        sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols        (such as, for example, Lanette®), sorbitan fatty acid esters        (such as, for example, Span®), polyoxyethylene sorbitan fatty        acid esters (such as, for example, Tween®), polyoxyethylene        fatty acid glycerides (such as, for example, Cremophor®),        polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol        ethers, glycerol fatty acid esters, poloxamers (such as, for        example, Pluronic®),    -   buffers, acids and bases (for example phosphates, carbonates,        citric acid, acetic acid, hydrochloric acid, sodium hydroxide        solution, ammonium carbonate, trometamol, triethanolamine),    -   isotonicity agents (for example glucose, sodium chloride),    -   adsorbents (for example highly-disperse silicas),    -   viscosity-increasing agents, gel formers, thickeners and/or        binders (for example polyvinylpyrrolidone, methylcellulose,        hydroxypropylmethylcellulose, hydroxypropylcellulose,        carboxymethylcellulose-sodium, starch, carbomers, polyacrylic        acids (such as, for example, Carbopol®); alginates, gelatine),    -   disintegrants (for example modified starch,        carboxymethylcellulose-sodium, sodium starch glycolate (such as,        for example, Explotab®), cross-linked polyvinylpyrrolidone,        croscarmellose-sodium (such as, for example, AcDiSol®)),    -   flow regulators, lubricants, glidants and mould release agents        (for example magnesium stearate, stearic acid, talc,        highly-disperse silicas (such as, for example, Aerosil®)),    -   coating materials (for example sugar, shellac) and film formers        for films or diffusion membranes which dissolve rapidly or in a        modified manner (for example polyvinylpyrrolidones (such as, for        example, Kollidon®), polyvinyl alcohol,        hydroxypropylmethylcellulose, hydroxypropylcellulose,        ethylcellulose, hydroxypropylmethylcellulose phthalate,        cellulose acetate, cellulose acetate phthalate, polyacrylates,        polymethacrylates such as, for example, Eudragit®)),    -   capsule materials (for example gelatine,        hydroxypropylmethylcellulose),    -   synthetic polymers (for example polylactides, polyglycolides,        polyacrylates, polymethacrylates (such as, for example,        Eudragit®), polyvinylpyrrolidones (such as, for example,        Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene        oxides, polyethylene glycols and their copolymers and        blockcopolymers),    -   plasticizers (for example polyethylene glycols, propylene        glycol, glycerol, triacetine, triacetyl citrate, dibutyl        phthalate),    -   penetration enhancers,    -   stabilisers (for example antioxidants such as, for example,        ascorbic acid, ascorbyl palmitate, sodium ascorbate,        butylhydroxyanisole, butylhydroxytoluene, propyl gallate),    -   preservatives (for example parabens, sorbic acid, thiomersal,        benzalkonium chloride, chlorhexidine acetate, sodium benzoate),    -   colourants (for example inorganic pigments such as, for example,        iron oxides, titanium dioxide),    -   flavourings, sweeteners, flavour- and/or odour-masking agents.

The present invention furthermore relates to a pharmaceuticalcomposition which comprise at least one compound according to theinvention, conventionally together with one or more pharmaceuticallysuitable excipient(s), and to their use according to the presentinvention.

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of cardiovascular and renal disorders, bystandard toxicity tests and by standard pharmacological assays for thedetermination of treatment of the conditions identified above inmammals, and by comparison of these results with the results of knownactive ingredients or medicaments that are used to treat theseconditions, the effective dosage of the compounds of the presentinvention can readily be determined for treatment of each desiredindication. The amount of the active ingredient to be administered inthe treatment of one of these conditions can vary widely according tosuch considerations as the particular compound and dosage unit employed,the mode of administration, the period of treatment, the age and sex ofthe patient treated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and preferably from about 0.01 mg/kg to about 20 mg/kg bodyweight per day. Clinically useful dosing schedules will range from oneto three times a day dosing to once every four weeks dosing. Inaddition, it is possible for “drug holidays”, in which a patient is notdosed with a drug for a certain period of time, to be beneficial to theoverall balance between pharmacological effect and tolerability. It ispossible for a unit dosage to contain from about 0.5 mg to about 1500 mgof active ingredient, and can be administered one or more times per dayor less than once a day. The average daily dosage for administration byinjection, including intravenous, intramuscular, subcutaneous andparenteral injections, and use of infusion techniques will preferably befrom 0.01 to 200 mg/kg of total body weight. Illustratively, thecompound of the present invention may be administered parenterally at adose of about 0.001 mg/kg to about 10 mg/kg, preferably of about 0.01mg/kg to about 1 mg/kg of body weight. In oral administration, anexemplary dose range is about 0.01 to 100 mg/kg, preferably about 0.01to 20 mg/kg, and more preferably about 0.1 to 10 mg/kg of body weight.Ranges intermediate to the above-recited values are also intended to bepart of the invention.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

The following exemplary embodiments illustrate the invention. Theinvention is not restricted to the examples.

The percentages in the following tests and examples are, unless statedotherwise, by weight; parts are by weight. Solvent ratios, dilutionratios and concentrations reported for liquid/liquid solutions are eachbased on volume.

EXPERIMENTAL SECTION

NMR peak forms are stated as they appear in the spectra, possible higherorder effects have not been considered.

Chemical names were generated using the ACD/Name software from ACD/Labs.In some cases generally accepted names of commercially availablereagents were used in place of ACD/Name generated names.

The following table 1 lists the abbreviations used in this paragraph andin the Examples section as far as they are not explained within the textbody. Other abbreviations have their meanings customary per se to theskilled person.

TABLE 1 Abbreviations The following table lists the abbreviations usedherein. Abbreviation Meaning AIBN azobisisobutyronitrile br broad(¹H-NMR signal) CI chemical ionisation d doublet DAD diode arraydetector DCM dichloromethane dd double-doublet DMSO dimethylsulfoxide dtdouble-triplet ELSD Evaporative Light Scattering Detector ESIelectrospray (ES) ionisation h hour(s) HCl hydrochloric acid HPLC highperformance liquid chromatography LC-MS liquid chromatography massspectrometry m multiplet min minute(s) MeOH methanol MS massspectrometry NBS N-bromosuccinimide NMR nuclear magnetic resonancespectroscopy: chemical shifts (δ) are given in ppm. The chemical shiftswere corrected by setting the DMSO signal to 2.50 ppm unless otherwisestated. of th. of theory PDA Photo Diode Array q quartet r.t. or rt orRT room temperature Rt retention time (as measured either with HPLC orUPLC) in minutes s singlet SFC supercritical fluid chromatography SQDSingle-Quadrupole-Detector t triplet td triple-doublet TFFAtrifluoroacetic acid anhydride THF tetrahydrofuran UPLC ultraperformance liquid chromatography

The various aspects of the invention described in this application areillustrated by the following examples which are not meant to limit theinvention in any way.

The example testing experiments described herein serve to illustrate thepresent invention and the invention is not limited to the examplesgiven.

EXPERIMENTAL SECTION—GENERAL PART

All reagents, for which the synthesis is not described in theexperimental part, are either commercially available, or are knowncompounds or may be formed from known compounds by known methods by aperson skilled in the art.

The compounds and intermediates produced according to the methods of theinvention may require purification. Purification of organic compounds iswell known to the person skilled in the art and there may be severalways of purifying the same compound. In some cases, no purification maybe necessary. In some cases, the compounds may be purified bycrystallization. In some cases, impurities may be stirred out using asuitable solvent. In some cases, the compounds may be purified bychromatography, particularly flash column chromatography, using forexample prepacked silica gel cartridges, e.g. Biotage SNAP cartidgesKP-Sil® or KP-NH® in combination with a Biotage autopurifier system(SP4® or Isolera One®) and eluents such as gradients of hexane/ethylacetate or DCM/methanol. In some cases, the compounds may be purified bypreparative HPLC using for example a Waters autopurifier equipped with adiode array detector and/or on-line electrospray ionization massspectrometer in combination with a suitable prepacked reverse phasecolumn and eluents such as gradients of water and acetonitrile which maycontain additives such as trifluoroacetic acid, formic acid or aqueousammonia.

In some cases, purification methods as described above can provide thosecompounds of the present invention which possess a sufficiently basic oracidic functionality in the form of a salt, such as, in the case of acompound of the present invention which is sufficiently basic, atrifluoroacetate or formate salt for example, or, in the case of acompound of the present invention which is sufficiently acidic, anammonium salt for example. A salt of this type can either be transformedinto its free base or free acid form, respectively, by various methodsknown to the person skilled in the art, or be used as salts insubsequent biological assays. It is to be understood that the specificform (e.g. salt, free base etc.) of a compound of the present inventionas isolated and as described herein is not necessarily the only form inwhich said compound can be applied to a biological assay in order toquantify the specific biological activity.

UPLC, HPLC and LC-MS Standard Procedures Method 1 (LC-MS):

Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; column: WatersAcquity UPLC HSS T3 1.8μ 50×2.1 mm; eluent A: 1 l of water+0.25 ml 99%strengh formic acid, eluent B: 1 l of acetonitrile+0.25 ml 99% strengthformic acid; gradient: 0.0 min 90% A→0.3 min 90% A→1.7 min 5% A→3.0 min5% A; oven: 50° C.; flow: 1.20 ml/min; UV detection: 205-305 nm.

Method 2 (LC-MS):

Instrument: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLCHSS T3 1.8μ 50×1 mm; eluent A: 1 l of water+0.25 ml 99% strength formicacid, eluent B: 1 l of acetonitrile+0.25 ml 99% strength formic acid;gradient: 0.0 min 90% A→1.2 min 5% A→2.0 min 5% A; oven: 50° C.; flow:0.40 ml/min; UV detection: 208-400 nm.

Method 3 (LC-MS):

Instrument: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLCHSS T3 1.8μ50×1 mm; eluent A: 1 l of waters+0.25 ml 99% strength formicacid, eluent B: 1 l of acetonitrile+0.25 ml 99% strength formic acid;gradient: 0.0 min 95% A→6.0 min 5% A→7.5 min 5% A; oven: 50° C.; flow:0.35 ml/min; UV detection: 210-400 nm.

Method 4 (LC-MS)

MS instrument type: Agilent Technologies 6130 Quadrupole LC-MS; HPLCinstrument type: Agilent Technologies 1260 Infinity; column: WatersXSelect (C18, 30×2.1 mm, 3.5 μm); flow: 1 ml/min; column temperature:35° C.; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1%formic acid in water; linear gradient: t=0 min 5% A, t=1.6 min 98% A,t=3 min 98% A; detection: DAD (220-320 nm); detection: MSD (ESI pos/neg)mass range: 100-800; detection: ELSD (PL-ELS 2100): gas flow 1.2 ml/min,gas temperature: 70° C.

Method 5 (LC-MS)

MS instrument type: Agilent Technologies LC-MSD SL; HPLC instrumenttype: Agilent Technologies 1100 Series; column: Waters XSelect (C18,50×2.1 mm, 3.5 μm; flow: 0.8 ml/min; column temperature: 25° C.; eluentA: 95% acetonitrile+5% ammoniumbicarbonate in water; eluent B: 10 mmMammoniumbicarbonate in water pH=9.0; linear gradient: t=0 min 5% A, t3.5 min 98% A, t=6 min 98% A; detection: DAD (220-320 nm); detection:MSD (ESI pos/neg) mass range: 100-800.

Method 6 (GC-MS)

Instrument: GC: Agilent 6890N, FID: detection temperature: 300° C. andMS: 5973 MSD, EI-positive, detection temperature: 280° C. mass range:50-550; column: RXi-5MS 20 m, ID 180 μm, df 0.18 μm; average velocity:50 cm/s; injection vol: 1 μl; injector temperature: 250° C.; splitratio: 20/1; carrier gas: He; initial temperature: 100° C.; initialtime: 1.5 min; solvent delay: 1.3 min; rate 75° C./min; finaltemperature 250° C.; Final time 2.5 min

Method 7 (Flash Chromatography)

Instrument: Reveleris™ Flash Chromatography System; columns:GraceResolv™ Silica Cartridge; 4 g, flow 5 ml/min; 12 g, flow 16 ml/min;40 g, flow 50 ml/min; 80 g, flow 100 ml/min; 120 g, flow 160 ml/min andDavisil™ Chromatographic Silica Media (LC60A 20-45 micron); 300 g, flow70 ml/min; 500 g, flow 70 ml/min; eluents: see experiment; detection: UV(200-360 nm), ELSD.

Method 8 (LC-MS):

Instrument MS: Thermo Scientific FT-MS; Instrument UHPLC+: ThermoScientific UltiMate 3000; column: Waters, HSST3, 2.1×75 mm, C18 1.8 μm;eluent A: 1 l of water+0.01% formic acid; eluent B: 1 l ofacetonitrile+0.01% formic acid; gradient: 0.0 min 10% B→2.5 min 95%B→3.5 min 95% B; oven: 50° C.; flow: 0.90 ml/min; UV detection: 210nm/Optimum Integration Path 210-300 nm.

Method 9 (preparative HPLC):

Column: Reprosil or Chromatorex; C18; 10 μm; 125×30 mm; eluent A: 101 ofwater+20 ml 50% formic acid, eluent B: acetonitrile; gradient: 0-5.50min 10% B: 90% A; sample injection: at 3.00 min; 5.50 min 90% A: 10%B→17.65 min 5% A: 95% B; 17.65-19.48 min 5% A: 95% B; flow: 75 ml/min;UV detection: 210 nm.

EXPERIMENTAL SECTION—STARTING MATERIALS AND INTERMEDIATES Example 1A{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetonitrile

In a 2 l reaction vessel, 100 g (273 mmol) of{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}aceticacid (synthesis described as Example 8A in WO 2010/105770-A1), 43.3 g(547 mmol) of pyridine and 33 mg (0.3 mmol) of 4-dimethylaminopyridinewere dissolved in 300 ml THF. The resulting solution was treated at 5°C. with 52.8 g (438 mmol) of 2,2-dimethylpropanoylchloride over 15minutes and the resulting mixture was stirred at room temperature for2.5 hours. After cooling to 0° C., 183 ml of 28% aqueous ammoniasolution was added over 1 h while the solution temperature was keptbetween 10° C. and 20° C. and at the resulting mixture then stirred at5° C. for an additional time period of 1 h. 500 ml methyltert-butylether and 300 ml 20% aqueous citric acid were then added whilekeeping the internal temperature between 10° C. and 20° C. The phaseswere then separated and the organic phase was washed with 300 ml of 20%aqueous citric acid followed by 300 ml saturated aqueous sodiumhydrogencarbonate solution and finally with 300 ml of 10% aqueous sodiumchloride solution. The organic phase was evaporated at 60° C. underreduced pressure until an oily residue was obtained. 300 ml THF was thenadded and the solution was evaporated again until an oily solution wasobtained. This operation was repeated a second time. The oil residue wasretaken in 360 ml THF and treated with 172 g (820 mmol) trifluoroaceticacid anhydride over 20 min at a temperature between 10° C. and 20° C.The resulting solution was then stirred at room temperature for 1 h. 720ml 4-methyl-2-pentanone and 650 ml 7.5% aqueous sodium hydroxidesolution were added at a temperature between 10° C. and 20° C. Finallythe pH-value was adjusted to pH=9.5 using 7.5% aqueous sodium hydroxidesolution. After phase separation, the organic phase was washed twicewith 450 ml 10% aqueous sodium chloride solution. The organic phase wasevaporated at a temperature of 80° C. under reduced pressure while 1200ml n-heptane was added. The formed suspension was cooled to 20° C. and asolid formed which was filtered off and washed with 200 ml n-heptane andthen dried under reduced pressure (50° C., 30 mbar) affording 88 g (93%of th.) of{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetonitrileas a solid.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.78 (d, 2H), 7.55 (d, 2H), 6.91 (d,1H), 5.17 (s, 2H), 4.34-4.23 (m, 1H), 3.98 (dd, 1H), 3.81 (dd, 1H).

Example 2AMethyl-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluor-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate

In a 41 reaction vessel, 200 g (576.9 mmol) of{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetonitrile(Example 1A) in 1600 ml methanol was treated with 5.2 g (28 mmol) sodiummethanolate (30% in methanol) and the resulting mixture was stirred at50° C. for 2.5 hours. The solution was then evaporated at 50° C. underreduced pressure until an oily solution was obtained. 2000 ml methyltert-butylether was added and the solution was concentrated until avolume of 800 ml was achieved. 3000 ml n-heptane was then added and asuspension was formed. After cooling at 20° C., the solid was filteredand washed with 500 ml n-heptane and then dried under reduced pressure(50° C., 30 mbar) affording 175 g (80% of th.) of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H1,2,4-triazol-1-yl}ethanimidateas a solid.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=8.01 (s, 1H), 7.78 (d, 2H), 7.62 (d,2H), 6.93 (br. s, 1H), 4.50 (s, 2H), 4.35-4.23 (m, 1H), 3.96 (dd, 1H),3.81 (dd, 1H), 3.67 (s, 3H).

Example 3A Methyl{3-(4-chlorophenyl)-5-oxo-4-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetate

Under argon, potassium tert-butoxide (9.12 g, 81.3 mmol) was addedportionwise at room temperature to a solution of5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 5A in WO 2011/104322-A1; 20 g, 65.0 mmol) in THF (40 ml). Tothis solution was added methyl bromoacetate (10.94 g, 71.5 mmol), andthe mixture was stirred at room temperature overnight. The reactionmixture was then diluted with water and extracted with ethyl acetate.The combined organic phases were dried over sodium sulfate, filtered,and concentrated in vacuo. 16.4 g (30.23 mmol) of the desired compoundwere obtained (47% of th.).

LC-MS (Method 2): R_(t)=0.90 min; MS (ESIpos): m/z=380 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=7.73-7.81 (m, 2H), 7.60-7.69 (m, 2H),6.92 (d, 1H), 4.72 (s, 2H), 4.19-4.33 (m, 1H), 4.00 (dd, 1H), 3.85 (dd,1H), 3.70 (s, 3H).

The title compound can also be synthesized via the procedure describedin WO 2011/104322-A1 (Example 7A).

Example 4A2-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetohydrazie

7.2 g (18.96 mmol) of methyl{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetate(Example 3A) were dissolved in (60 ml) absolute ethanol. To thissolution were added 2.09 g (41.71 mmol) of hydrazine hydrate, and themixture was stirred under reflux for 5 h and then at room temperatureovernight. The resulting mixture was partially concentrated in vacuo andthen diluted with water and extracted with ethyl acetate. The combinedorganic phases were dried over sodium sulfate, filtered, andconcentrated in vacuo. The residue was dissolved in dichloromethane, andafter crystallization the white solid was filtered off and dried underhigh vacuum. 7.02 g (98% of th.) of the desired compound were obtained.

LC-MS (Method 2): R_(t)=0.73 min; MS (ESIpos): m/z=380 [M+H]⁺

¹H NMR (400 MHz, DMSO-d6): δ [ppm] 9.23 (t, 1H), 7.73-7.78 (m, 2H),7.61-7.66 (m, 2H), 6.90 (d, 1H), 4.38 (d, 2H), 4.24-4.34 (m, 3H), 3.96(dd, 1H), 3.82 (dd, 1H).

Example 5A5-(4-Chlorophenyl)-2-{[5-(difluoromethyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Under argon, sodium ethoxide (280 mg, 3.95 mmol, 96% purity) was addedportionwise at room temperature to a solution of2-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetohydrazie(Example 4A, 750 mg, 1.98 mmol) and 2,2-difluoroethanimidamide (204 mg,2.17 mmol) in dimethylformamide (21 ml). The reaction mixture wasirradiated for 1.5 h at 150° C. under microwave irradiation. Aftercooling, the reaction mixture was diluted with tert-butyl-methyletherand then quenched with aqueous HCl (0.5 M). After phase separation, theaqueous phase was extracted twice with tert-butyl-methylether. Thecombined organic phases were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude was purified bypreparative HPLC (Method 9) and 225 mg (25% of th.) of the titlecompound were obtained.

LC-MS (Method 2): R_(t)=0.89 min; MS (ESIpos): m/z=439 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=14.66 (br. s., 1H), 7.73-7.79 (m, 2H),7.61-7.66 (m, 2H), 7.07 (t, 1H), 6.92 (d, 1H), 5.20 (br. s., 2H),4.25-4.43 (m, 1H), 3.98 (dd, 1H), 3.83 (dd, 1H).

Example 6A N′-(3-Fluorophenyl)ethanimidohydrazie

To a solution of (3-fluorophenyl)hydrazine hydrochloride (10 g, 61.5mmol) in methanol (30 ml) were added triethylamine (62 g, 615 mmol, 85ml) and acetamidine hydrochloride (29 g, 308 mmol). The reaction mixturewas stirred at room temperature for 18 h. Triethylamine (31 g, 308 mmol,43 ml) and acetamidine hydrochloride (15 g, 154 mmol) were added andstirring was continued for 72 h. Water (300 ml) and ethyl acetate (500ml) were added. Layers were separated and aqueous layer was extractedwith ethyl acetate. Combined organic extracts were washed with brine,dried with sodium sulfate and solvents were removed in vacuo. The crudeproduct was purified by flash column chromatography (Method 7; 80 g;dichloromethane, 0%-10% methanol). 2.6 g (25% of th.) of the titlecompound were obtained.

GC-MS (Method 6): R_(t)=4.00 min; MS (ESIpos): m/z=167 [M+H]⁺

Example 7A1-(3-Fluorophenyl)-3-methyl-5-(trifluoromethyl)-1H-1,2,4-triazole

Under nitrogen atmosphere at room temperature 2,2,2-trifluoroaceticanhydride (16.3 g, 78 mmol, 10.8 ml) was added to a solution ofN′-(3-fluorophenyl)ethanimidohydrazie (Example 6A, 2.6 g, 15.5 mmol) in1,4-dioxane (100 ml). Stirring was continued for 1.5 h. Reaction mixturewas partitioned between water (250 ml) and ethyl acetate (300 ml).Organic layer was washed with brine and dried with sodium sulfate.Solvents were removed in vacuo. Flash column chromatography (Method 7;80 g; heptane, 0%-50% ethyl acetate) afforded 2.9 g (76% of th.) of thetitle compound.

LC-MS (Method 4): R_(t)=1.99 min; MS (ESIpos): m/z=246 [M+H]⁺

Example 8A3-(Bromomethyl)-1-(3-fluorophenyl)-5-(trifluoromethyl)-1H-1,2,4-triazole

To a solution of1-(3-fluorophenyl)-3-methyl-5-(trifluoromethyl)-1H-1,2,4-triazole(Example 7A, 2.5 g, 10.2 mmol) in acetonitrile (100 ml) were addedN-bromosuccinimide (9.1 g, 51.0 mmol) and2,2′-azobis(2-methylpropionitrile) (0.8 g, 5.1 mmol). The reactionmixture was stirred at reflux for 16 h and was allowed to cool to roomtemperature. Solvents were removed in vacuo and the residue was absorbedon isolute. Purification by flash column chromatography (Method 7; 120g; toluene, 0%-5% ethyl acetate) afforded 512 mg (14.7% of th.) of thetitle compound.

LC-MS (Method 5): R_(t)=3.2 min; MS (ESIpos): m/z=322/324 [M+H]⁺

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=7.61-7.44 (m, 4H), 4.56 (s, 2H).

Example 9A N′-(2-Chlorophenyl)ethanimidohydrazie

To a solution of (2-chlorophenyl)hydrazine hydrochloride (13.8 g, 77mmol) and ethyl ethanimidoate hydrochloride (9.5 g, 77 mmol) in ethanol(250 ml) was added anhydrous sodium acetate (12.6 g, 154 mmol). Theresulting suspension was stirred at reflux for 1 h. The suspension wasconcentrated to a volume of approximately 100 ml and was diluted withdichloromethane. The mixture was washed with water and subsequently withbrine and was dried with sodium sulfate. Solvents were removed in vacuo.The crude product was absorbed on isolute and purified by flash columnchromatography (Method 7; 120 g; dichloromethane/ammonia [7N in MeOH]).5.9 g (41% of th.) of the title compound were obtained.

GC-MS (Method 6): R_(t)=4.29 min; MS (ESIpos): m/z=184 [M+H]⁺.

Example 10A1-(2-Chlorophenyl)-3-methyl-5-(trifluoromethyl)-1H-1,2,4-triazole

Under nitrogen atmosphere at room temperature 2,2,2-trifluoroaceticanhydride (26.3 g, 125 mmol, 17 ml) was added to a solution ofN′-(2-chlorophenyl)ethanimidohydrazie (Example 9A, 4.6 g, 25.0 mmol) in1,4-dioxane (150 ml). Stirring was continued for 1.5 h. Reaction mixturewas partitioned between water (250 ml) and ethyl acetate (300 ml).Organic layer was washed with brine and dried with sodium sulfate.Solvents were removed in vacuo. Flash column chromatography (Method 7;80 g; heptane, 0%-50% ethyl acetate) afforded 6.55 g (quant.) of thetitle compound.

LC-MS (Method 4): R_(t)=1.98 min; MS (ESIpos): m/z=262 [M+H]⁺

Example 11A3-(Bromomethyl)-1-(2-chlorophenyl)-5-(trifluoromethyl)-1H-1,2,4-triazole

To a solution of1-(2-chlorophenyl)-3-methyl-5-(trifluoromethyl)-1H-1,2,4-triazole(Example 10A, 6.5 g, 24.8 mmol) in acetonitrile (100 ml) were addedN-bromosuccinimide (22.11 g, 124 mmol) and2,2′-azobis(2-methylpropionitrile) (2.04 g, 12.4 mmol). The reactionmixture was stirred at reflux for 16 h and was allowed to cool to roomtemperature. Solvents were removed in vacuo and the residue was absorbedon isolute. Purification by flash column chromatography (Method 7; 120g; toluene, 0%-5% ethyl acetate) afforded 1.3 g (15% of th.) of thetitle compound.

LC-MS (Method 5): R_(t)=3.32 min; MS (ESIpos): m/z=340/342 [M+H]⁺

Example 12A1-(2-Chlorophenyl)-5-(difluoromethyl)-3-methyl-1H-1,2,4-triazole

Under nitrogen atmosphere at room temperature 2,2-difluoroaceticanhydride (5.00 g, 28.7 mmol, 3.57 ml) was added to a solution ofN′-(2-chlorophenyl)ethanimidohydrazie (Example 9A, 1.75 g, 9.6 mmol) in1,4-dioxane (50 ml). Stirring was continued for 1.5 h. Reaction mixturewas partitioned between water (100 ml) and ethyl acetate (100 ml).Organic layer was washed with brine and dried with sodium sulfate.Solvents were removed in vacuo. Flash column chromatography (Method 7;80 g; heptane, 0%-50% ethyl acetate) afforded 1.67 g (6.85 mmol; 71% ofth.) of the title compound.

LC-MS (Method 4): R_(t)=1.85 min; MS (ESIpos): m/z=244 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.56-7.49 (m, 4H), 7.32-7.23 (m, 3H),4.54 (s, 2H).

Example 13A3-(Bromomethyl)-1-(2-chlorophenyl)-5-(difluoromethyl)-1H-1,2,4-triazole

To a solution of1-(2-chlorophenyl)-5-(difluoromethyl)-3-methyl-1H-1,2,4-triazole(Example 12A, 1.76 g, 7.2 mmol) in acetonitrile (100 ml) were addedN-bromosuccinimide (6.43 g, 36.1 mmol) and2,2′-azobis(2-methylpropionitrile) (0.59 g, 3.6 mmol). The reactionmixture was stirred at reflux for 16 h and was allowed to cool to roomtemperature. Solvents were removed in vacuo and the residue was absorbedon isolute. Purification by flash column chromatography (Method 7; 40 g;toluene, 0%-5% ethyl acetate) afforded 0.22 g (batch 1) of the titlecompound. 1.10 g of starting material was recovered.

The recovered1-(2-chlorophenyl)-5-(difluoromethyl)-3-methyl-1H-1,2,4-triazole (1.10g, 4.5 mmol) was dissolved in acetonitrile (100 ml). N-bromosuccinimide(4.00 g, 22.5 mmol) and 2,2′-azobis(2-methylpropionitrile) (0.37 g, 2.3mmol) were added. The mixture was stirred at reflux for 16 h and wasallowed to cool to room temperature. Solvents were removed in vacuo andthe residue was absorbed on isolute. Purification by flash columnchromatography (Method 7; 40 g; toluene, 0%-5% ethyl acetate) afforded0.20 g (batch 2) of the title compound. 0.80 g of starting material wasrecovered.

The recovered1-(2-chlorophenyl)-5-(difluoromethyl)-3-methyl-1H-1,2,4-triazole (0.80g, 3.3 mmol) was dissolved in acetonitrile (50 ml). N-bromosuccinimide(4.00 g, 22.5 mmol) and 2,2′-azobis(2-methylpropionitrile) (0.37 g, 2.3mmol) were added. The mixture was stirred at reflux for 16 h and wasallowed to cool to room temperature. Solvents were removed in vacuo andthe residue was absorbed on isolute. Purification by flash columnchromatography (Method 7; 12 g; toluene, 0%-5% ethyl acetate) afforded0.15 g (batch 3) of the title compound.

Batches 1, 2 and 3 were combined and purified by flash columnchromatography (Method 7; 40 g; dichloromethane, 0%-5% methanol). 0.392g (1.18 mmol; 16% of th.) of the title compound were obtained.

LC-MS (Method 5): Rt=3.42 min; MS (ESIpos): m/z=322/324 [M+H]⁺

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=7.61-7.44 (m, 4H), 6.73 (t, 1H), 4.56(s, 2H).

Example 14A 2-Fluoropropanoyl Chloride

2-fluoropropanoic acid (42.1 mg, 457 μmol) and1-chloro-N,N,2-trimethylprop-1-en-1-amine (79 μl, 590 μmol) weredissolved in THF (460 μl, 5.6 mmol) and stirred for 30 min at roomtemperature. The resulting mixture was directly used in the followingstep.

Example 15A 2,2-Difluoropropanoyl Chloride

2,2-difluoropropanoic acid (71.0 mg, 645 μmol) and1-chloro-N,N,2-trimethylprop-1-en-1-amine (110 μl, 840 μmol) weredissolved in THF (750 μl, 9.2 mmol) and stirred for 30 min at roomtemperature. The resulting mixture was directly used in the followingstep.

Example 16A Difluoro(1-hydroxycyclopentyl)acetyl chloride

Difluoro(1-hydroxycyclopentyl)acetic acid (synthesis described inWO2015/005901 A1, page 575-576; 200 mg, 1.11 mmol) and1-chloro-N,N,2-trimethylprop-1-en-1-amine (223 mg, 1.67 mmol) weredissolved in THF (1.6 ml) and stirred for 30 min at room temperature.The resulting mixture was directly used in the following step.

Example 17A3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-2,2-difluoropropanoic acid

3-Amino-2,2-difluoropropanoic acid hydrochloride (1:1) (550 mg, 3.40mmol), 2-benzofuran-1,3-dione (630 mg, 4.26 mmol) and triethylamine (590μl, 4.3 mmol) were dissolved in toluene (400 μl) heated under relux for4 h. The solvent was removed in vauo and the residue was directly usedin the following step.

Example 18A3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-2,2-difluoropropanoylChloride

3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2,2-difluoropropanoic acid(Example 17A, 200 mg, 784 μmol) and1-chloro-N,N,2-trimethylprop-1-en-1-amine (190 μl, 1.4 mmol) weredissolved in (780 μl) THF and stirred for 30 min at room temperature.The resulting mixture was directly used in the following step.

Example 19A Difluoro(tetrahydro-2H-pyran-4-yl)acetyl chloride

Difluoro(tetrahydro-2H-pyran-4-yl)acetic acid (synthesis described inWO2006/095020 A1, page 47; 100 mg, 555 μmol) and1-chloro-N,N,2-trimethylprop-1-en-1-amine (95 μl, 720 μmol) weredissolved in (560 μl) THF and stirred for 30 min at room temperature.The resulting mixture was directly used in the following step.

Example 20A2-{2-[1-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]-2,2-difluoroethyl}-1H-isoindole-1,3(2H)-dione

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 237 mg, 626 μmol) in THF (4.7 ml) was cooled to 0° C. andtreated with3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-2,2-difluoropropanoylchloride (Example 18A, 214 mg, 783 μmol) in 500 μl THF andN,N-diisopropylethylamine (135 μl, 0.8 mmol). The resulting mixture wasstirred for 30 min After (2-chlorophenyl)hydrazine hydrochloride (1:1)(123 mg, 689 μmol) and N,N-diisopropylethylamine (135 μl, 0.8 mmol) wereadded, the reaction mixture was warmed up to room temperature andstirred for 1 h, followed by 2 h at 120° C. in a sealed vial undermicrowave irradiation. The crude product was purified by preparativeHPLC (Method 9). Lyophilisation of the product containing fractionsafforded 150 mg (34% of th.) of the title compound as solid.

LC-MS (Method 1): R_(t)=1.48 min; MS (ESIpos): m/z=708 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.94-7.83 (m, 3H), 7.83-7.69 (m, 3H),7.69-7.58 (m, 3H), 7.58-7.49 (m, 1H), 6.90 (d, 1H), 5.26-5.08 (m, 2H),4.47 (br s, 2H), 4.38-4.21 (m, 1H), 4.09-3.95 (m, 1H), 3.85 (dd, 1H).

EXPERIMENTAL SECTION—EXAMPLES Example 15-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 150 mg, 396 μmol) in THF (3.0 ml) was cooled to 0° C. andtreated with 2-fluoropropanoyl chloride (Example 14A, 54.7 mg, 495 μmol)in 500 μl THF and N,N-diisopropylethylamine (86 μl, 500 μmol). Theresulting mixture was stirred for 30 min After (2-chlorophenyl)hydrazinehydrochloride (1:1) (78.0 mg, 436 μmol) and N,N-diisopropylethylamine(76 μl, 440 μmol) were added, the reaction mixture was warmed up to roomtemperature and stirred for 1 h, followed by 30 min at 100° C. and 30min at 120° C. in a sealed vial under microwave irradiation. The crudeproduct was purified by preparative HPLC (Method 9). Lyophilisation ofthe product containing fractions afforded 166 mg (77% of th.) of thetitle compound as solid and as a mixture of diastereomers.

LC-MS (Method 3): R_(t)=1.06 min; MS (ESIpos): m/z=545 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.79-7.72 (m, 3H), 7.72-7.64 (m, 2H),7.63 (d, 2H), 7.60-7.53 (m, 1H), 6.89 (dd, 1H), 5.73-5.54 (m, 1H),5.27-5.03 (m, 2H), 4.30 (br d, 1H), 4.12-3.94 (m, 1H), 3.85 (dd, 1H),1.72-1.57 (m, 3H).

The two diastereomers were separated by preparative chiral HPLC [samplepreparation: 120 mg dissolved in 2 ml ethanol; injection volume: 0.1 ml;column: Daicel Chirallpak® OD-H, 5 μm, 250×20 mm; eluent:n-heptane/i-propanol 90:10; flow rate: 20 ml/min; temperature: 23° C.;UV detection: 220 nm]. After separation, 45.1 mg of diastereomer 1(Example 2), which eluted first, and 67.4 mg of diastereomer 2 (Example3), which eluted later, were isolated.

Example 25-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomer 1)

Analytical chiral HPLC: R_(t)=2.26 min, d.e.=100% [column: Phenomenexcellulose-1 50×4.6 mm; eluent: i-hexane/ethanol 90/10, flow rate: 1ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=2.01 min; MS (ESIpos): m/z=545 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.79-7.49 (m, 8H), 6.89 (d, 1H),5.75-5.52 (m, 1H), 5.23-5.06 (m, 2H), 4.35-4.22 (m, 1H), 4.06-3.96 (m,1H), 3.85 (dd, 1H), 1.73-1.54 (m, 3H).

Example 35-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(diastereomer 2)

Analytical chiral HPLC: R_(t)=2.00 min, d.e.=95% [column: Phenomenexcellulose-1 50×4.6 mm; eluent: i-hexane/ethanol 90/10, flow rate: 1ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=2.01 min; MS (ESIpos): m/z=545 [M+H]+

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 7.82-7.51 (m, 8H), 6.90 (d, 1H),5.71-5.53 (m, 1H), 5.20-5.05 (m, 2H), 4.29 (br d, 1H), 4.01 (dd, 1H),3.85 (dd, 1H), 1.72-1.57 (m, 3H).

Example 45-(4-Chlorophenyl)-2-({1-(4-chloropyridin-3-yl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 150 mg, 396 μmol) in THF (3.0 ml) was cooled to 0° C. andtreated with 2-fluoropropanoyl chloride (Example 14A, 54.7 mg, 495 μmol)in 500 μl THF and N,N-diisopropylethylamine (86 μl, 500 μmol). Theresulting mixture was stirred for 30 min After4-chloro-3-hydrazinylpyridine hydrochloride (1:1) (78.4 mg, 436 μmol)and N,N-diisopropylethylamine (76 μl, 440 μmol) were added, the reactionmixture was warmed up to room temperature and stirred over night,followed by 1 h at 120° C. in a sealed vial under microwave irradiation.The crude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 68.7 mg (31%of th.) of the title compound as solid and as a mixture ofdiastereomers.

LC-MS (Method 8): R_(t)=1.77 min; MS (ESIpos): m/z=546 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.88 (s, 1H), 8.78 (d, 1H), 7.90 (d,1H), 7.75 (d, 2H), 7.63 (d, 2H), 6.90 (d, 1H), 5.91-5.66 (m, 1H), 5.15(d, 2H), 4.29 (br d, 1H), 4.13-3.93 (m, 1H), 3.85 (dd, 1H), 1.73-1.61(m, 3H).

The two diastereomers were separated by preparative chiral HPLC [samplepreparation: 60 mg dissolved in 6 ml ethanol; injection volume: 0.3 ml;column: Daicel Chirallpak® IA, 5 μm, 250×20 mm; eluent: i-hexane/ethanol70:30; flow rate: 20 ml/min; temperature: 30° C.; UV detection: 220 nm].After separation, 26.0 mg of diastereomer 1 (Example 5), which elutedfirst, and 28.0 mg of diastereomer 2 (Example 6), which eluted later,were isolated.

Example 55-(4-Chlorophenyl)-2-({1-(4-chloropyridin-3-yl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomer 1)

Analytical chiral HPLC: R_(t)=8.95 min, d.e.=100% [column: DaicelChirallpak® IA 250×4.6 mm; eluent: i-hexane/ethanol 70/30, flow rate: 1ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=1.80 min; MS (ESIpos): m/z=546 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.88 (s, 1H), 8.78 (d, 1H), 7.90 (d,1H), 7.80-7.69 (m, 2H), 7.69-7.50 (m, 2H), 6.89 (d, 1H), 5.94-5.65 (m,1H), 5.14 (d, 2H), 4.29 (br d, 1H), 4.09-3.93 (m, 1H), 3.85 (dd, 1H),1.75-1.57 (m, 3H).

Example 65-(4-Chlorophenyl)-2-({1-(4-chloropyridin-3-yl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(diastereomer 2)

Analytical chiral HPLC: R_(t)=10.40 min, d.e.=100% [column: DaicelChirallpak® IA 250×4.6 mm; eluent: i-hexane/ethanol 70/30, flow rate: 1ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=1.80 min; MS (ESIpos): m/z=546 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.88 (s, 1H), 8.78 (d, 1H), 7.90 (d,1H), 7.81-7.68 (m, 2H), 7.68-7.49 (m, 2H), 6.90 (d, 1H), 5.98-5.58 (m,1H), 5.15 (d, 2H), 4.29 (br d, 1H), 4.08-3.93 (m, 1H), 3.85 (dd, 1H),1.75-1.55 (m, 3H).

Example 75-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-[4-(trifluoromethyl)pyridin-3-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 150 mg, 396 μmol) in THF (3.0 ml) was cooled to 0° C. andtreated with 2-fluoropropanoyl chloride (Example 14A, 54.7 mg, 495 μmol)in 500 μl THF and N,N-diisopropylethylamine (86 μl, 500 μmol). Theresulting mixture was stirred for 30 min After3-hydrazinyl-4-(trifluoromethyl)pyridine (77.2 mg, 436 μmol) andN,N-diisopropylethylamine (76 μl, 440 μmol) were added, the reactionmixture was warmed up to room temperature and stirred for 1 h, followedby 1 h at 120° C. and 1 h at 140° C. in a sealed vial under microwaveirradiation. The crude product was purified by preparative HPLC (Method9). Lyophilisation of the product containing fractions afforded 142 mg(61% of th.) of the title compound as solid and as a mixture ofdiastereomers.

LC-MS (Method 1): R_(t)=1.31 min; MS (ESIpos): m/z=580 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.11 (d, 1H), 9.07 (s, 1H), 8.08 (d,1H), 7.80-7.69 (m, 2H), 7.68-7.59 (m, 2H), 6.89 (d, 1H), 5.96-5.71 (m,1H), 5.21-5.04 (m, 2H), 4.29 (br d, 1H), 4.08-3.94 (m, 1H), 3.94-3.80(m, 1H), 1.72-1.61 (m, 3H).

The two diastereomers were separated by preparative chiral HPLC [samplepreparation: 135 mg dissolved in 3 ml methanol; injection volume: 0.3ml; column: Daicel Chiralpak® IA 5 μm, 250×30 mm; eluent:isohexane/ethanol 80:20; flow rate: 30 ml/min; temperature: 30° C.; UVdetection: 220 nm]. After two separations, 59.0 mg of diastereomer 1(Example 7), which eluted first, and 56.0 mg of diastereomer 2 (Example8), which eluted later, were isolated.

Example 85-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-[4-(trifluoromethyl)pyridin-3-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomer 1)

Analytical chiral HPLC: R_(t)=8.98 min, d.e.=99% [column: DaicelChirallpak® IA 250×4.6 mm; eluent: i-hexane/ethanol 80/20, flow rate: 1ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=1.90 min; MS (ESIpos): m/z=580 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.11 (d, 1H), 9.07 (s, 1H), 8.08 (d,1H), 7.79-7.68 (m, 2H), 7.68-7.55 (m, 2H), 6.89 (d, 1H), 5.95-5.69 (m,1H), 5.21-5.03 (m, 2H), 4.36-4.17 (m, 1H), 4.09-3.94 (m, 1H), 3.85 (dd,1H), 1.73-1.57 (m, 3H).

Example 95-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-[4-(trifluoromethyl)pyridin-3-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomer 2)

Analytical chiral HPLC: R_(t)=9.95 min, d.e.=99% [column: DaicelChirallpak® IA 250×4.6 mm; eluent: i-hexane/ethanol 80/20, flow rate: 1ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=1.89 min; MS (ESIpos): m/z=580 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.11 (d, 1H), 9.07 (s, 1H), 8.08 (d,1H), 7.81-7.69 (m, 2H), 7.66-7.54 (m, 2H), 6.89 (d, 1H), 6.01-5.68 (m,1H), 5.38-4.97 (m, 2H), 4.29 (br d, 1H), 4.08-3.95 (m, 1H), 3.91-3.81(m, 1H), 1.70-1.58 (m, 3H).

Example 105-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 1.00 g, 2.64 mmol) in 1,4-dioxane (30 ml) was cooled to 10°C. and treated with 2-fluoropropanoyl chloride (Example 14A, 365 mg,3.30 mmol) in 500 μl THF and N,N-diisopropylethylamine (570 μl, 3.3mmol). The resulting mixture was stirred for 30 min. A prestirredsolution of (506 mg, 3.17 mmol),1):2-hydrazinyl-3-(trifluoromethyl)pyridine 4-methylbenzenesulfonate(1:1) (1.11 g, 3.17 mmol) and N,N-diisopropylethylamine (550 μl, 3.2mmol) in (10 ml) 1,4-dioxane was added to the reaction mixture and wasstirred overnight at room temperature. Water were added, the aqueousphase was extracted with ethyl acetate, the combined organic phases werewashed with sodium chloride solution, dried over magnesium sulfate andevaporated in vacuo. The crude product was purified by chromatography(silica gel, cyclohexane/ethyl acetate, gradient) followed bypreparative HPLC (Method 9). Lyophilisation of the product containingfractions afforded 123 mg (9% of th.) of the title compound as solid andas a mixture of diastereomers.

LC-MS (Method 1): R_(t)=1.33 min; MS (ESIpos): m/z=580 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.92 (dd, 1H), 8.57 (dd, 1H), 7.94(dd, 1H), 7.74 (d, 2H), 7.66-7.57 (m, 3H), 6.89 (dd, 1H), 6.02-5.85 (m,1H), 5.18-5.08 (m, 2H), 4.35-4.25 (m, 1H), 3.99 (dd, 1H), 3.84 (dd, 1H),1.72-1.62 (m, 3H), 1.34-1.22 (m, 1H)

The two diastereomers were separated by preparative chiral HPLC [samplepreparation: 132 mg dissolved in 6 ml ethanol; injection volume: 0.3 ml;column: Daicel Chirallpak® IF, 5 μm, 250×20 mm; eluent: n-heptan/ethanol50:50; flow rate: 20 ml/min; temperature: 30° C.; UV detection: 220 nm].After separation, 44.0 mg of diastereomer 1 (Example 11), which elutedfirst, and 42.0 mg of diastereomer 2 (Example 12), which eluted later,were isolated.

Example 115-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(diastereomer 1)

Analytical chiral HPLC: R_(t)=6.19 min, d.e.=99% [column: DaicelChirallpak® IA 250×4.6 mm; eluent: i-hexane/ethanol 70/30, flow rate: 1ml/min; UV detection: 220 nm].

LC-MS (Method 1): R_(t)=1.34 min; MS (ESIpos): m/z=580 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.92 (dd, 1H), 8.57 (dd, 1H),8.00-7.89 (m, 1H), 7.81-7.68 (m, 2H), 7.68-7.57 (m, 2H), 6.89 (s, 1H),6.09-5.81 (m, 1H), 5.19-5.02 (m, 2H), 4.40-4.18 (m, 1H), 4.07-3.93 (m,1H), 3.84 (dd, 1H), 1.74-1.57 (m, 3H).

Example 125-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomer 2)

Analytical chiral HPLC: R_(t)=12.06 min, d.e.=99% [column: DaicelChirallpak® IA 250×4.6 mm; eluent: i-hexane/ethanol 70/30, flow rate: 1ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=1.94 min; MS (ESIpos): m/z=580 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.92 (dd, 1H), 8.57 (dd, 1H), 7.94(dd, 1H), 7.81-7.67 (m, 2H), 7.67-7.59 (m, 2H), 6.89 (br d, 1H),6.10-5.80 (m, 1H), 5.27-5.02 (m, 2H), 4.29 (br s, 1H), 4.12-3.93 (m,1H), 3.84 (dd, 1H), 1.76-1.57 (m, 3H).

Example 135-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 150 mg, 396 μmol) in THF (3.0 ml) was cooled to 0° C. andtreated with 2-fluoropropanoyl chloride (Example 14A, 54.7 mg, 495 μmol)in 500 μl THF and N,N-diisopropylethylamine (86 μl, 500 μmol). Theresulting mixture was stirred for 30 min After (3-fluorophenyl)hydrazinehydrochloride (1:1) (70.8 mg, 436 μmol) and N,N-diisopropylethylamine(76 μl, 440 μmol) were added, the reaction mixture was warmed up to roomtemperature and stirred for 30 min, followed by 2 h at 140° C. in asealed vial under microwave irradiation. The crude product was purifiedby preparative HPLC (Method 9). Lyophilisation of the product containingfractions afforded 120 mg (57% of th.) of the title compound as solidand as a mixture of diastereomers. The mixture of diastereomers weredirectly submitted to chiral separation.

The two diastereomers were separated by preparative chiral HPLC [samplepreparation: 120 mg dissolved in 2 ml acetonitrile; injection volume:0.05 ml; column: Daicel Chirallpak® ID, 5 μm, 250×20 mm; eluent:isohexane/ethanol 80:20; flow rate: 20 ml/min; temperature: 23° C.; UVdetection: 220 nm]. After separation, 31.1 mg of diastereomer 1 (Example14), which eluted first, and 28.9 mg of diastereomer 2 (Example 15),which eluted later, were isolated.

Example 145-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(diastereomer 1)

Analytical chiral HPLC: R_(t)=1.22 min, d.e.=99% [column: DaicelChirallpak® ID-3 50×4.6 mm; eluent: n-heptane/ethanol 80/20, flow rate:1 ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=1.98 min; MS (ESIpos): m/z=529 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.78-7.73 (m, 2H), 7.69-7.60 (m, 3H),7.51 (dt, 1H), 7.47-7.40 (m, 2H), 6.89 (d, 1H), 6.00-5.76 (m, 1H), 5.12(s, 2H), 4.30 (br d, 1H), 4.09-3.92 (m, 1H), 3.85 (dd, 1H), 1.79-1.63(m, 3H).

Example 155-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomer 2)

Analytical chiral HPLC: R_(t)=1.42 min, d.e.=99% [column: DaicelChirallpak® ID-3 50×4.6 mm; eluent: n-heptane/ethanol 80/20, flow rate:1 ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=1.98 min; MS (ESIpos): m/z=529 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.78-7.73 (m, 2H), 7.70-7.60 (m, 3H),7.51 (dt, 1H), 7.47-7.41 (m, 2H), 6.89 (d, 1H), 6.07-5.72 (m, 1H), 5.12(d, 2H), 4.39-4.17 (m, 1H), 4.07-3.94 (m, 1H), 3.85 (dd, 1H), 1.80-1.65(m, 3H).

Example 165-(4-Chlorophenyl)-2-({1-(3-chlorophenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 150 mg, 396 μmol) in N,N-diisopropylethylamine (86 μl, 500μmol) was cooled to 0° C. and treated with 2-fluoropropanoyl chloride(Example 14A, 54.7 mg, 495 μmol) in 500 μl THF andN,N-diisopropylethylamine (76 μl, 440 μmol). The resulting mixture wasstirred for 30 min After (3-chlorophenyl)hydrazine hydrochloride (1:1)(78.0 mg, 436 μmol) and N,N-diisopropylethylamine (86 μl, 500 μmol) wereadded, the reaction mixture was warmed up to room temperature andstirred for 1 h, followed by 1 h at 140° C. in a sealed vial undermicrowave irradiation. The crude product was purified by preparativeHPLC (Method 9). Lyophilisation of the product containing fractionsafforded 134 mg (62% of th.) of the title compound as solid and as amixture of diastereomers.

LC-MS (Method 3): R_(t)=1.16 min; MS (ESIpos): m/z=545 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.78-7.73 (m, 2H), 7.71-7.69 (m, 1H),7.68-7.63 (m, 2H), 7.64-7.60 (m, 2H), 7.59-7.54 (m, 1H), 6.89 (d, 1H),6.01-5.77 (m, 1H), 5.12 (s, 2H), 4.30 (br d, 1H), 4.05-3.96 (m, 1H),3.85 (dd, 1H), 1.78-1.65 (m, 3H).

The two diastereomers were separated by preparative chiral HPLC [samplepreparation: 90 mg dissolved in 2.5 ml acetonitrile; injection volume:0.05 ml; column: Daicel Chirallpak® IF, 5 μm, 250×20 mm; eluent:n-heptan/ethanol 70:30; flow rate: 20 ml/min; temperature: 23° C.; UVdetection: 220 nm]. After separation, 49.2 mg of diastereomer 1 (Example17), which eluted first, and 45.7 mg of diastereomer 2 (Example 18),which eluted later, were isolated.

Example 175-(4-Chlorophenyl)-2-({1-(3-chlorophenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomer 1)

Analytical chiral HPLC: R_(t)=2.28 min, d.e.=99% [column: DaicelChirallpak® IF-3 50×4.6 mm; eluent: n-heptane/ethanol 80/20, flow rate:1 ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=2.08 min; MS (ESIpos): m/z=545 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.77-7.73 (m, 2H), 7.71-7.69 (m, 1H),7.68-7.60 (m, 4H), 7.58-7.54 (m, 1H), 6.89 (br s, 1H), 5.98-5.74 (m,1H), 5.12 (s, 2H), 4.37-4.24 (m, 1H), 4.09-3.96 (m, 1H), 3.85 (dd, 1H),1.83-1.60 (m, 3H).

Example 185-(4-Chlorophenyl)-2-({1-(3-chlorophenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomer 2)

Analytical chiral HPLC: R_(t)=3.80 min, d.e.=83% [column: DaicelChirallpak® IF-3 50×4.6 mm; eluent: n-heptane/ethanol 80/20, flow rate:1 ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=2.08 min; MS (ESIpos): m/z=545 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.75 (d, 2H), 7.70 (d, 1H), 7.67-7.60(m, 4H), 7.59-7.54 (m, 1H), 6.89 (d, 1H), 6.04-5.75 (m, 1H), 5.12 (d,2H), 4.30 (br d, 1H), 4.10-3.93 (m, 1H), 3.85 (dd, 1H), 1.76-1.62 (m,3H).

Example 195-(4-Chlorophenyl)-2-({1-(3-chloropyridin-2-yl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 1.00 g, 2.64 mmol) in in 1,4-dioxane (30 ml) was cooled to10° C. and treated with 2-fluoropropanoyl chloride (Example 14A, 365 mg,3.30 mmol) in 500 μl THF and N,N-diisopropylethylamine (570 μl, 3.3mmol). The resulting mixture was stirred for 30 min A prestirredsolution of (506 mg, 3.17 mmol), 3-chloro-2-hydrazinylpyridine (455 mg,3.17 mmol) and N,N-diisopropylethylamine (570 μl, 3.3 mmol) and in1,4-dioxane (10 ml) was added to the reaction mixture and was stirredovernight at room temperature. Water were added, the aqueous phase wasextracted with ethyl acetate, the combined organic phases were washedwith sodium chloride solution, dried over magnesium sulfate andevaporated in vacuo. The crude product was purified by chromatography(silica gel, cyclohexane/ethyl acetate, gradient) followed bypreparative HPLC (Method 9). Lyophilisation of the product containingfractions afforded 850 mg (53% of th.) of the title compound as solidand as a mixture of diastereomers.

LC-MS (Method 8): R_(t)=1.88 min; MS (ESIpos): m/z=546 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.62 (dd, 1H), 8.33 (dd, 1H),7.77-7.70 (m, 3H), 7.67-7.59 (m, 2H), 6.89 (d, 1H), 6.01-5.73 (m, 1H),5.15 (d, 2H), 4.35-4.21 (m, 1H), 4.11-3.96 (m, 1H), 3.85 (dd, 1H),1.74-1.60 (m, 3H).

The two diastereomers were separated by preparative chiral SCF [samplepreparation: 806 mg dissolved in 20 ml methanol; injection volume: 0.2ml; column: Daicel Chirallpak® IC, 5 μm, 250×20 mm; eluent: CO₂/methanol88:12; flow rate: 80 ml/min; temperature: 40° C.; UV detection: 210 nm].After separation, 314 mg of diastereomer 1 (Example 20), which elutedfirst, and 323 mg of diastereomer 2 (Example 21), which eluted later,were isolated.

Example 205-(4-Chlorophenyl)-2-({1-(3-chloropyridin-2-yl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomer 1)

Analytical chiral HPLC (SFC): R_(t)=1.02 min, d.e.=100% [column: DaicelChirallpak® IC 20×4.6 mm; eluent: carbon dioxide/methanol 80/20; flowrate: 3 ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=1.85 min; MS (ESIpos): m/z=546 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.62 (dd, 1H), 8.33 (dd, 1H),7.81-7.69 (m, 4H), 7.69-7.52 (m, 2H), 6.90 (br s, 1H), 5.96-5.76 (m,1H), 5.14 (d, 2H), 4.39-4.23 (m, 1H), 4.12-3.96 (m, 1H), 3.85 (dd, 1H),1.78-1.52 (m, 4H).

Example 215-(4-Chlorophenyl)-2-({1-(3-chloropyridin-2-yl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomer 2)

Analytical chiral HPLC (SFC): R_(t)=1.23 min, d.e.=100% [column: DaicelChirallpak® IC 20×4.6 mm; eluent: carbon dioxide/methanol 80/20; flowrate: 3 ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=1.85 min; MS (ESIpos): m/z=546 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.62 (dd, 1H), 8.33 (dd, 1H),7.85-7.69 (m, 3H), 7.66-7.58 (m, 2H), 6.89 (s, 1H), 6.01-5.73 (m, 1H),5.14 (d, 2H), 4.36-4.20 (m, 1H), 4.07-3.94 (m, 1H), 3.85 (dd, 1H),1.75-1.59 (m, 3H).

Example 225-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-[2-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 151 mg, 400 μmol) in THF (3.0 ml,) was cooled to 0° C. andtreated with 2-fluoropropanoyl chloride (Example 14A, 55.3 mg, 500 μmol)in 500 μl THF and N,N-diisopropylethylamine (87 μl, 500 μmol). Theresulting mixture was stirred for 30 min After[2-(trifluoromethyl)phenyl]hydrazine hydrochloride (1:1) (93.5 mg, 440μmol) and N,N-diisopropylethylamine (77 μl, 440 μmol) were added, thereaction mixture was warmed up to room temperature and stirred for 1 h,followed by 2 h at 120° C. in a sealed vial under microwave irradiation.The crude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 112 mg (44%of th.) of the title compound as solid and as a mixture ofdiastereomers.

LC-MS (Method 8): R_(t)=2.02 min; MS (ESIpos): m/z=579 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.00 (dd, 1H), 7.95-7.83 (m, 2H),7.81-7.71 (m, 3H), 7.66-7.60 (m, 2H), 6.89 (dd, 1H), 5.78-5.53 (m, 1H),5.21-5.04 (m, 2H), 4.29 (br d, 1H), 4.06-3.96 (m, 1H), 3.85 (dd, 1H),1.71-1.57 (m, 3H).

The two diastereomers were separated by preparative chiral HPLC [samplepreparation: 105.9 mg dissolved in 2.0 ml methanol; injection volume:0.1 ml; column: Daicel Chirallpak® IA, 5 μm, 250×20 mm; eluent:tert-butyl-methylether/methanol 95:5; flow rate: 20 ml/min; temperature:23° C.; UV detection: 220 nm]. After separation, 31.1 mg of diastereomer1 (Example 23), which eluted first, and 33.5 mg of diastereomer 2(Example 24), which eluted later, were isolated.

Example 235-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-[2-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomer 1)

Analytical chiral HPLC: R_(t)=10.61 min, d.e.=100% [column: DaicelChirallpak® IA 250×4.6 mm; eluent: tert-butyl methyl ether/methanol95/5, flow rate: 1 ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=2.01 min; MS (ESIpos): m/z=579 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.00 (dd, 1H), 7.95-7.81 (m, 2H),7.81-7.68 (m, 3H), 7.68-7.44 (m, 2H), 6.89 (d, 1H), 5.84-5.49 (m, 1H),5.22-4.86 (m, 2H), 4.28 (br s, 1H), 4.10-3.92 (m, 1H), 3.85 (dd, 1H),1.75-1.53 (m, 3H).

Example 245-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-[2-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomer 2)

Analytical chiral HPLC: R_(t)=9.72 min, d.e.=100% [column: DaicelChirallpak® IA 250×4.6 mm; eluent: tert-butyl methyl ether/methanol95/5, flow rate: 1 ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=2.01 min; MS (ESIpos): m/z=579 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.05-7.96 (m, 1H), 7.96-7.81 (m, 2H),7.81-7.69 (m, 3H), 7.69-7.57 (m, 2H), 6.89 (s, 1H), 5.79-5.54 (m, 1H),5.22-5.03 (m, 2H), 4.29 (br s, 1H), 4.09-3.94 (m, 1H), 3.90-3.78 (m,1H), 1.72-1.51 (m, 3H).

Example 255-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-[2-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 151 mg, 400 μmol) in THF (3.0 ml) was cooled to 0° C. andtreated with 2-fluoropropanoyl chloride (Example 14A, 55.3 mg, 500 μmol)in 500 μl THF and N,N-diisopropylethylamine (87 μl, 500 μmol). Theresulting mixture was stirred for 30 min After[2-(trifluoromethoxy)phenyl]hydrazine hydrochloride (1:1) (101 mg, 440μmol) and N,N-diisopropylethylamine (77 μl, 440 μmol) were added, thereaction mixture was warmed up to room temperature and stirred for 1 h,followed by 2 h at 120° C. in a sealed vial under microwave irradiation.The crude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 99.8 mg (38%of th.) of the title compound as solid and as a mixture ofdiastereomers.

LC-MS (Method 8): R_(t)=2.07 min; MS (ESIpos): m/z=595 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.79-7.71 (m, 4H), 7.67 (dt, 1H),7.64-7.58 (m, 3H), 6.89 (d, 1H), 5.85-5.54 (m, 1H), 5.23-5.07 (m, 2H),4.38-4.22 (m, 1H), 4.05-3.94 (m, 1H), 3.85 (dd, 1H), 1.72-1.61 (m, 3H).

The two diastereomers were separated by preparative chiral HPLC [samplepreparation: 95.2 mg dissolved in 2.5 ml ethanol; injection volume: 0.10ml; column: Daicel Chirallpak® IA, 5 μm, 250×20 mm; eluent:tert-butyl-methylether/methanol 90:10; flow rate: 15 ml/min;temperature: 25° C.; UV detection: 220 nm]. After separation, 40.6 mg ofdiastereomer 1 (Example 26), which eluted first, and 40.0 mg ofdiastereomer 2 (Example 27), which eluted later, were isolated.

Example 265-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-[2-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomer 1)

Analytical chiral HPLC: R_(t)=5.16 min, d.e.=93% [column: DaicelChirallpak® IA 250×4.6 mm; eluent: tert-butyl methyl ether/acetonitrile90/10, flow rate: 1 ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=2.09 min; MS (ESIpos): m/z=595 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.78-7.71 (m, 4H), 7.67 (dt, 1H),7.64-7.59 (m, 3H), 6.89 (d, 1H), 5.84-5.56 (m, 1H), 5.20-5.05 (m, 2H),4.39-4.22 (m, 1H), 4.06-3.95 (m, 1H), 3.85 (dd, 1H), 1.73-1.58 (m, 3H).

Example 275-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-[2-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomer 2)

Analytical chiral HPLC: R_(t)=6.41 min, d.e.=90% [column: DaicelChirallpak® IA 250×4.6 mm; eluent: tert-butyl methyl ether/acetonitrile90/10, flow rate: 1 ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=2.09 min; MS (ESIpos): m/z=595 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.79-7.71 (m, 4H), 7.67 (dt, 1H),7.65-7.59 (m, 3H), 6.89 (d, 1H), 5.82-5.49 (m, 1H), 5.12 (d, 2H), 4.29(br d, 1H), 4.09-3.93 (m, 1H), 3.85 (dd, 1H), 1.76-1.54 (m, 3H).

Example 285-(4-Chlorophenyl)-2-({1-(2-ethylphenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 151 mg, 400 μmol) in THF (3.0 ml) was cooled to 0° C. andtreated with 2-fluoropropanoyl chloride (Example 14A, 55.3 mg, 500 μmol)in 500 μl THF and N,N-diisopropylethylamine (87 μl, 500 μmol). Theresulting mixture was stirred for 30 min After (2-ethylphenyl)hydrazinehydrochloride (1:1) (76.0 mg, 440 μmol) and N,N-diisopropylethylamine(77 μl, 440 μmol) were added, the reaction mixture was warmed up to roomtemperature and stirred for 1 h, followed by 2 h at 120° C. in a sealedvial under microwave irradiation. The crude product was purified bypreparative HPLC (Method 9). Lyophilisation of the product containingfractions afforded 126 mg (54% of th.) of the title compound as solidand as a mixture of diastereomers.

LC-MS (Method 8): R_(t)=2.10 min; MS (ESIpos): m/z=539 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.74 (d, 2H), 7.65-7.60 (m, 2H),7.59-7.52 (m, 1H), 7.51-7.46 (m, 1H), 7.43-7.36 (m, 2H), 6.89 (dd, 1H),5.70-5.43 (m, 1H), 5.24-5.02 (m, 2H), 4.39-4.18 (m, 1H), 4.06-3.94 (m,1H), 3.85 (dd, 1H), 2.26 (q, 2H), 1.75-1.57 (m, 3H), 0.97 (t, 3H).

The two diastereomers were separated by preparative chiral HPLC [samplepreparation: 120.5 mg dissolved in 2.5 ml methanol; injection volume:0.05 ml; column: Daicel Chirallpak® IA, 5 μm, 250×20 mm; eluent:tert-butyl-methylether/methanol 95:5; flow rate: 20 ml/min; temperature:23° C.; UV detection: 220 nm]. After separation, 26.7 mg of diastereomer1 (Example 29), which eluted first, and 27.7 mg of diastereomer 2(Example 30), which eluted later, were isolated.

Example 295-(4-Chlorophenyl)-2-({1-(2-ethylphenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(diastereomer 1)

Analytical chiral HPLC: R_(t)=8.97 min, d.e.=100% [column: DaicelChirallpak® IA 250×4.6 mm; eluent: tert-butyl methyl ether, flow rate: 1ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=2.09 min; MS (ESIpos): m/z=539 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.76-7.72 (m, 2H), 7.62 (d, 2H),7.58-7.52 (m, 1H), 7.50-7.45 (m, 1H), 7.43-7.36 (m, 2H), 6.89 (d, 1H),5.71-5.44 (m, 1H), 5.12 (s, 2H), 4.37-4.22 (m, 1H), 4.08-3.92 (m, 1H),3.92-3.77 (m, 1H), 2.26 (q, 2H), 1.75-1.54 (m, 3H), 0.97 (t, 3H).

Example 305-(4-Chlorophenyl)-2-({1-(2-ethylphenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(diastereomer 2)

Analytical chiral HPLC: R_(t)=10.30 min, d.e.=97% [column: DaicelChirallpak® IA 250×4.6 mm; eluent: tert-butyl methyl ether, flow rate: 1ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=2.09 min; MS (ESIpos): m/z=539 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.77-7.69 (m, 2H), 7.67-7.59 (m, 2H),7.58-7.50 (m, 1H), 7.50-7.45 (m, 1H), 7.45-7.35 (m, 2H), 6.88 (d, 1H),5.68-5.45 (m, 1H), 5.22-5.04 (m, 2H), 4.29 (br d, 1H), 4.07-3.95 (m,1H), 3.85 (dd, 1H), 2.26 (q, 2H), 1.75-1.57 (m, 3H), 0.97 (t, 3H).

Example 31

5-(4-Chlorophenyl)-2-({1-[2-(difluoromethoxy)phenyl]-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 151 mg, 400 μmol) in THF (3.0 ml) was cooled to 0° C. andtreated with 2-fluoropropanoyl chloride (Example 14A, 55.3 mg, 500 μmol)in 500 μl THF and N,N-diisopropylethylamine (87 μl, 500 μmol). Theresulting mixture was stirred for 30 min After[2-(difluoromethoxy)phenyl]hydrazine (76.6 mg, 440 μmol) andN,N-diisopropylethylamine (87 μl, 500 μmol) were added, the reactionmixture was warmed up to room temperature and stirred for 1 h, followedby 2 h at 120° C. in a sealed vial under microwave irradiation. Thecrude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 103 mg (45%of th.) of the title compound as solid and as a mixture ofdiastereomers.

LC-MS (Method 8): R_(t)=1.97 min; MS (ESIpos): m/z=577 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.83-7.58 (m, 6H), 7.51-7.36 (m, 2H),7.23 (s, 0.5H), 7.04 (s, 0.25H), 6.89 (dd, 1H), 5.77-5.54 (m, 1H),5.32-4.97 (m, 2H), 4.30 (br d, 1H), 4.09-3.92 (m, 1H), 3.85 (dd, 1H),1.72-1.58 (m, 3H)

The two diastereomers were separated by preparative chiral HPLC [samplepreparation: 198.4 mg dissolved in 3.0 ml ethanol; injection volume:0.15 ml; column: Daicel Chirallpak® IA, 5 μm, 250×20 mm; eluent:tert-butyl-methylether/methanol 90:10; flow rate: 15 ml/min;temperature: 25° C.; UV detection: 220 nm]. After separation, 41.8 mg ofdiastereomer 1 (Example 32), which eluted first, and 47.0 mg ofdiastereomer 2 (Example 33), which eluted later, were isolated.

Example 325-(4-Chlorophenyl)-2-({1-[2-(difluoromethoxy)phenyl]-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomer 1)

Analytical chiral HPLC: Rt=5.67 min, d.e.=100% [column: DaicelChirallpak® IA 250×4.6 mm; eluent: tert-butyl methyl ether/acetonitrile90/10, flow rate: 1 ml/min; UV detection: 220 nm].

LC-MS (Method 8): Rt=1.97 min; MS (ESIpos): m/z=577 [M+H]⁺

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.78-7.73 (m, 2H), 7.71-7.65 (m, 1H),7.65-7.60 (m, 3H), 7.49-7.40 (m, 2H), 7.22 (s, 0.56H), 7.04 (s, 0.25H),6.89 (d, 1H), 5.74-5.54 (m, 1H), 5.23-5.05 (m, 2H), 4.39-4.18 (m, 1H),4.13-3.97 (m, 1H), 3.85 (dd, 1H), 1.72-1.54 (m, 3H)

Example 335-(4-Chlorophenyl)-2-({1-[2-(difluoromethoxy)phenyl]-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomer 2)

Analytical chiral HPLC: Rt=6.88 min, d.e.=90% [column: DaicelChirallpak® IA 250×4.6 mm; eluent: tert-butyl methyl ether/acetonitrile90/10, flow rate: 1 ml/min; UV detection: 220 nm].

LC-MS (Method 8): Rt=1.98 min; MS (ESIpos): m/z=577 [M+H]⁺

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.77-7.73 (m, 2H), 7.71-7.65 (m, 1H),7.65-7.59 (m, 3H), 7.49-7.40 (m, 2H), 7.23 (s, 0.54H), 7.04 (s, 0.25H),6.90 (d, 1H), 5.79-5.51 (m, 1H), 5.12 (s, 2H), 4.30 (br d, 1H),4.06-3.95 (m, 1H), 3.85 (dd, 1H), 1.74-1.57 (m, 3H).

Example 345-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-(2-methylphenyl)-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 151 mg, 400 μmol) in THF (3.0 ml) was cooled to 0° C. andtreated with 2-fluoropropanoyl chloride (Example 14A, 55.3 mg, 500 μmol)in 500 μl THF and N,N-diisopropylethylamine (87 μl, 500 μmol). Theresulting mixture was stirred for 30 min. After(2-methylphenyl)hydrazine hydrochloride (1:1) (69.8 mg, 440 μmol) andN,N-diisopropylethylamine (77 μl, 440 μmol) were added, the reactionmixture was warmed up to room temperature and stirred for 1 h, followedby 2 h at 120° C. in a sealed vial under microwave irradiation. Thecrude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 129 mg (61%of th.) of the title compound as solid and as a mixture ofdiastereomers.

LC-MS (Method 8): R_(t)=2.00 min; MS (ESIpos): m/z=525 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.75 (d, 2H), 7.68-7.58 (m, 2H),7.57-7.34 (m, 4H), 6.89 (dd, 1H), 5.68-5.42 (m, 1H), 5.18-5.02 (m, 2H),4.37-4.21 (m, 1H), 4.06-3.93 (m, 1H), 3.85 (dd, 1H), 1.97 (s, 3H),1.73-1.57 (m, 3H).

The two diastereomers were separated by preparative chiral HPLC [samplepreparation: 124.7 mg dissolved in 3 ml tert-butyl-methylether;injection volume: 0.3 ml; column: YMC Chiralalart® Amylose SA, 5 μm,250×30 mm; eluent: tert-butyl-methylether/methanol 95:5; flow rate: 30ml/min; temperature: 30° C.; UV detection: 220 nm]. After separation,57.0 mg of diastereomer 1 (Example 35), which eluted first, and 56.0 mgof diastereomer 2 (Example 36), which eluted later, were isolated.

Example 355-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-(2-methylphenyl)-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(diastereomer 1)

Analytical chiral HPLC: R_(t)=8.42 min, d.e.=99% [column: YMC ChiralartAmylose SA 250×4.6 mm; eluent: tert-butyl methyl ether/methanol 95/5,flow rate: 1 ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=2.00 min; MS (ESIpos): m/z=525 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.80-7.68 (m, 2H), 7.68-7.56 (m, 2H),7.56-7.30 (m, 4H), 6.89 (s, 1H), 5.75-5.42 (m, 1H), 5.12 (s, 2H),4.34-4.21 (m, 1H), 4.09-3.96 (m, 1H), 3.85 (dd, 1H), 1.97 (s, 3H),1.76-1.55 (m, 3H).

Example 365-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-(2-methylphenyl)-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(diastereomer 2)

Analytical chiral HPLC: R_(t)=11.19 min, d.e.=99% [column: YMC ChiralartAmylose SA 250×4.6 mm; eluent: tert-butyl methyl ether/methanol 95/5,flow rate: 1 ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=2.00 min; MS (ESIpos): m/z=525 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.79-7.71 (m, 2H), 7.70-7.57 (m, 2H),7.57-7.33 (m, 4H), 6.89 (s, 1H), 5.67-5.41 (m, 1H), 5.19-5.05 (m, 2H),4.41-4.16 (m, 1H), 4.10-3.95 (m, 1H), 3.85 (dd, 1H), 1.97 (s, 3H),1.77-1.56 (m, 3H).

Example 375-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-(2-nitrophenyl)-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 202 mg, 533 μmol) in THF (4.0 ml) was cooled to 0° C. andtreated with 2-fluoropropanoyl chloride (Example 14A, 73.6 mg, 666 μmol)in 500 μl THF and N,N-diisopropylethylamine (120 μl, 670 μmol). Theresulting mixture was stirred for 30 min After (2-nitrophenyl)hydrazine(89.8 mg, 586 μmol) were added, the reaction mixture was warmed up toroom temperature and stirred for 30 min, followed by 1 h at 120° C., 3 hat 130° C. and 4 h at 150° C. in a sealed vial under microwaveirradiation. The crude product was purified by preparative HPLC (Method9). Lyophilisation of the product containing fractions afforded 38.8 mg(12% of th.) of the title compound as solid and as a mixture ofdiastereomers.

LC-MS (Method 8): R_(t)=1.88 min; MS (ESIpos): m/z=556 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.30-8.22 (m, 1H), 8.07-7.93 (m, 1H),7.93-7.83 (m, 2H), 7.80-7.69 (m, 2H), 7.68-7.57 (m, 2H), 6.89 (d, 1H),6.01-5.73 (m, 1H), 5.19-5.01 (m, 2H), 4.36-4.24 (m, 1H), 4.09-3.94 (m,1H), 3.84 (dd, 1H), 1.75-1.60 (m, 3H).

Example 382-{3-({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-1-yl}benzonitrile(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 202 mg, 533 μmol) in THF (4.0 ml) was cooled to 0° C. andtreated with 2-fluoropropanoyl chloride (Example 14A, 73.6 mg, 666 μmol)in 500 μl THF and N,N-diisopropylethylamine (120 μl, 670 μmol). Theresulting mixture was stirred for 30 min After 2-hydrazinylbenzonitrile(78.0 mg, 586 μmol) and N,N-diisopropylethylamine (120 μl, 670 μmol)were added, the reaction mixture was warmed up to room temperature andstirred for 30 min, followed by 3 h at 120° C. in a sealed vial undermicrowave irradiation. The crude product was purified by preparativeHPLC (Method 9). Lyophilisation of the product containing fractionsafforded 49.6 mg (16% of th.) of the title compound as solid and as amixture of diastereomers.

LC-MS (Method 8): R_(t)=2.07 min; MS (ESIpos): m/z=536 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.21 (d, 1H), 7.93 (d, 1H), 7.84-7.71(m, 3H), 7.71-7.57 (m, 2H), 7.38 (dd, 1H), 6.93 (dd, 1H), 6.77-6.53 (m,1H), 5.53-5.33 (m, 2H), 4.34 (br s, 1H), 4.16-4.02 (m, 1H), 3.99-3.88(m, 1H), 1.95-1.76 (m, 3H).

The two diastereomers were separated by preparative chiral HPLC [samplepreparation: 44.4 mg dissolved in 2.0 ml ethanol; injection volume: 0.2ml; column: Daicel Chirallpak® AZ-H, 5 μm, 250×20 mm; eluent:n-heptan/ethanol 70:30; flow rate: 20 ml/min; temperature: 25° C.; UVdetection: 220 nm]. After separation, 12.7 mg of diastereomer 1 (Example39), which eluted first, and 10.8 mg of diastereomer 2 (Example 40),which eluted later, were isolated.

Example 392-{3-({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-1-yl}benzonitrile(Diastereomer 1)

Analytical chiral HPLC: R_(t)=2.01 min, d.e.=100% [column: DaicelChirallpak® AZ-3 50×4.6 mm; eluent: n-heptane/ethanol 80/20, flow rate:1 ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=2.04 min; MS (ESIpos): m/z=536 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.21 (d, 1H), 7.93 (d, 1H), 7.84-7.72(m, 3H), 7.63 (d, 2H), 7.42-7.31 (m, 1H), 6.94 (br d, 1H), 6.81-6.52 (m,1H), 5.50-5.36 (m, 2H), 4.34 (br s, 1H), 4.16-4.03 (m, 1H), 3.99-3.88(m, 1H), 1.93-1.78 (m, 3H).

Example 402-{3-({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-1-yl}benzonitrile(Diastereomer 2)

Analytical chiral HPLC: R_(t)=3.43 min, d.e.=100% [column: DaicelChirallpak® AZ-3 50×4.6 mm; eluent: n-heptane/ethanol 80/20, flow rate:1 ml/min; UV detection: 220 nm].

LC-MS (Method 8): R_(t)=2.04 min; MS (ESIpos): m/z=536 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.21 (d, 1H), 7.93 (d, 1H), 7.85-7.70(m, 3H), 7.63 (d, 2H), 7.43-7.32 (m, 1H), 6.93 (br d, 1H), 6.75-6.47 (m,1H), 5.50-5.34 (m, 2H), 4.37-4.37 (m, 1H), 4.34 (br s, 1H), 4.16-4.04(m, 1H), 4.03-3.85 (m, 1H), 1.94-1.77 (m, 3H).

Example 412-{3-({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-1-yl}benzenesulfonamide(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 202 mg, 533 μmol) in THF (4.0 ml) was cooled to 0° C. andtreated with 2-fluoropropanoyl chloride (Example 14A, 73.6 mg, 666 μmol)in 500 μl THF and N,N-diisopropylethylamine (120 μl, 670 μmol). Theresulting mixture was stirred for 30 min. After2-hydrazinylbenzenesulfonamide (110 mg, 586 μmol) were added, thereaction mixture was warmed up to room temperature and stirred for 30min, followed by 2 h at 120° C. and 4 h at 140° C. in a sealed vialunder microwave irradiation. The crude product was purified bypreparative HPLC (Method 9). Lyophilisation of the product containingfractions afforded 155.3 mg (47% of th.) of the title compound as solidand as a mixture of diastereomers.

LC-MS (Method 8): R_(t)=1.75 min; MS (ESIpos): m/z=590 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.15-8.02 (m, 1H), 7.89-7.70 (m, 4H),7.70-7.55 (m, 3H), 7.19 (br s, 2H), 6.89 (t, 1H), 5.77-5.40 (m, 1H),5.27-4.98 (m, 2H), 4.30 (br d, 1H), 4.08-3.92 (m, 1H), 3.84 (dd, 1H),1.72-1.54 (m, 3H).

Example 425-(4-Chlorophenyl)-2-({1-(2-ethoxyphenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 202 mg, 533 μmol) in THF (4.0 ml) was cooled to 0° C. andtreated with 2-fluoropropanoyl chloride (Example 14A, 73.6 mg, 666 μmol)in 500 μl THF and N,N-diisopropylethylamine (120 μl, 670 μmol). Theresulting mixture was stirred for 30 min After (2-ethoxyphenyl)hydrazinehydrochloride (1:1) (111 mg, 586 μmol) and N,N-diisopropylethylamine(120 μl, 670 μmol) were added, the reaction mixture was warmed up toroom temperature and stirred for 30 min, followed by 3 h at 120° C. in asealed vial under microwave irradiation. The crude product was purifiedby preparative HPLC (Method 9). Lyophilisation of the product containingfractions afforded 43.8 mg (15% of th.) of the title compound as solidand as a mixture of diastereomers.

LC-MS (Method 8): R_(t)=2.04 min; MS (ESIpos): m/z=555 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.75 (d, 2H), 7.62 (d, 2H), 7.57-7.48(m, 1H), 7.41 (dd, 1H), 7.26 (d, 1H), 7.10 (t, 1H), 6.95-6.83 (m, 1H),5.83-5.83 (m, 1H), 5.67-5.42 (m, 1H), 5.16-5.02 (m, 2H), 4.30 (br d,1H), 4.17-3.96 (m, 3H), 3.85 (dd, 1H), 1.71-1.58 (m, 3H), 1.15 (t, 3H).

Example 435-(4-Chlorophenyl)-2-({1-(2,6-dichlorophenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 200 mg, 528 μmol) in THF (4.0 ml) was cooled to 0° C. andtreated with 2-fluoropropanoyl chloride (Example 14A, 72.9 mg, 660 μmol)in 500 μl THF and N,N-diisopropylethylamine (100 μl, 580 μmol). Theresulting mixture was stirred for 30 min After(2,6-dichlorophenyl)hydrazine hydrochloride (1:1) (124 mg, 581 μmol) andN,N-diisopropylethylamine (110 μl, 660 μmol) were added, the reactionmixture was warmed up to room temperature and stirred for 1 h, followedby 3 h at 120° C. in a sealed vial under microwave irradiation. Thecrude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 133 mg (43%of th.) of the title compound as solid and as a mixture ofdiastereomers.

LC-MS (Method 8): R_(t)=2.06 min; MS (ESIpos): m/z=579 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.80-7.73 (m, 4H), 7.71-7.66 (m, 1H),7.65-7.61 (m, 2H), 6.89 (br s, 1H), 5.92-5.57 (m, 1H), 5.27-5.05 (m,2H), 4.29 (br s, 1H), 4.09-3.95 (m, 1H), 3.86 (dd, 1H), 1.72-1.56 (m,3H).

Example 442-({1-(2-chloro-6-fluorophenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-5-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 200 mg, 528 μmol) in THF (4.0 ml) was cooled to 0° C. andtreated with 2-fluoropropanoyl chloride (Example 14A, 72.9 mg, 660 μmol)in 500 μl THF and N,N-diisopropylethylamine (100 μl, 580 μmol). Theresulting mixture was stirred for 30 min After(2-chloro-6-fluorophenyl)hydrazine hydrochloride (1:1) (114 mg, 581μmol) and N,N-diisopropylethylamine (110 μl, 660 μmol) were added, thereaction mixture was warmed up to room temperature and stirred for 1 h,followed by 3 h at 120° C. in a sealed vial under microwave irradiation.The crude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 192 mg (64%of th.) of the title compound as solid and as a mixture ofdiastereomers.

LC-MS (Method 8): R_(t)=2.00 min; MS (ESIpos): m/z=563 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.78-7.70 (m, 3H), 7.66-7.55 (m, 4H),6.89 (br s, 1H), 5.95-5.59 (m, 1H), 5.15 (d, 2H), 4.29 (br s, 1H),4.13-3.92 (m, 1H), 3.91-3.79 (m, 1H), 1.79-1.52 (m, 3H).

Example 455-(4-Chlorophenyl)-2-({1-(2,6-difluorophenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 200 mg, 528 μmol) in THF (4.0 ml) was cooled to 0° C. andtreated with 2-fluoropropanoyl chloride (Example 14A, 72.9 mg, 660 μmol)in 500 μl THF and N,N-diisopropylethylamine (110 μl, 660 μmol). Theresulting mixture was stirred for 1 h. After(2,6-difluorophenyl)hydrazine hydrochloride (1:1) (105 mg, 581 μmol) andN,N-diisopropylethylamine (100 μl, 580 μmol) were added, the reactionmixture was warmed up to room temperature and stirred for 1 h, followedby 3 h at 120° C. in a sealed vial under microwave irradiation. Thecrude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 175 mg (61%of th.) of the title compound as solid and as a mixture ofdiastereomers.

LC-MS (Method 8): R_(t)=1.96 min; MS (ESIpos): m/z=547 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.86-7.68 (m, 3H), 7.69-7.58 (m, 2H),7.45 (t, 2H), 6.89 (d, 1H), 5.95-5.68 (m, 1H), 5.14 (d, 2H), 4.28 (br s,1H), 4.13-3.97 (m, 1H), 3.85 (dd, 1H), 1.76-1.55 (m, 3H).

Example 465-(4-Chlorophenyl)-2-({1-(2,6-dimethylphenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 200 mg, 528 μmol) in THF (4.0 ml) was cooled to 0° C. andtreated with 2-fluoropropanoyl chloride (Example 14A, 72.9 mg, 660 μmol)in 500 μl THF and N,N-diisopropylethylamine (110 μl, 660 μmol). Theresulting mixture was stirred for 1 h. After(2,6-dimethylphenyl)hydrazine hydrochloride (1:1) (100 mg, 581 μmol) andN,N-diisopropylethylamine (100 μl, 580 μmol) were added, the reactionmixture was warmed up to room temperature and stirred for 1 h, followedby 3 h at 120° C. in a sealed vial under microwave irradiation. Thecrude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 73.1 mg (24%of th.) of the title compound as solid and as a mixture ofdiastereomers.

LC-MS (Method 8): R_(t)=2.08 min; MS (ESIpos): m/z=539 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.73 (d, 2H), 7.67-7.58 (m, 2H),7.45-7.34 (m, 1H), 7.27 (d, 2H), 6.89 (d, 1H), 5.59-5.33 (m, 1H),5.23-5.06 (m, 2H), 4.29 (br d, 1H), 4.06-3.95 (m, 1H), 3.85 (dd, 1H),1.90 (s, 3H), 1.87 (s, 3H), 1.71-1.55 (m, 3H).

Example 475-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-[2-(propan-2-yl)phenyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 200 mg, 528 μmol) in THF (4.0 ml) was cooled to 0° C. andtreated with 2-fluoropropanoyl chloride (Example 14A, 72.9 mg, 660 μmol)in 500 μl THF and N,N-diisopropylethylamine (100 μl, 580 μmol). Theresulting mixture was stirred for 1 h. After[2-(propan-2-yl)phenyl]hydrazine hydrochloride (1:1) (108 mg, 581 μmol)and N,N-diisopropylethylamine (110 μl, 660 μmol) were added, thereaction mixture was warmed up to room temperature and stirred for 1 h,followed by 3 h at 120° C. in a sealed vial under microwave irradiation.The crude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 190 mg (65%of th.) of the title compound as solid and as a mixture ofdiastereomers.

LC-MS (Method 3): R_(t)=1.22 min; MS (ESIpos): m/z=553 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.74 (d, 2H), 7.67-7.52 (m, 4H),7.45-7.30 (m, 2H), 6.89 (d, 1H), 5.72-5.45 (m, 1H), 5.13 (d, 2H), 4.29(br d, 1H), 4.11-3.93 (m, 1H), 3.91-3.78 (m, 1H), 2.35 (quin, 1H),1.73-1.55 (m, 3H), 1.08-0.98 (m, 6H).

Example 485-(4-Chlorophenyl)-2-({1-(2-ethyl-6-methylphenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 200 mg, 528 μmol) in THF (4.0 ml) was cooled to 0° C. andtreated with 2-fluoropropanoyl chloride (Example 14A, 72.9 mg, 660 μmol)in 500 μl THF and N,N-diisopropylethylamine (100 μl, 580 μmol). Theresulting mixture was stirred for 1 h. After(2-ethyl-6-methylphenyl)hydrazine hydrochloride (1:1) (108 mg, 581 μmol)and N,N-diisopropylethylamine (110 μl, 660 μmol) were added, thereaction mixture was warmed up to room temperature and stirred for 1 h,followed by 3 h at 120° C. in a sealed vial under microwave irradiation.The crude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 17.8 mg (6%of th.) of the title compound as solid and as a mixture ofdiastereomers.

LC-MS (Method 3): R_(t)=1.21 min; MS (ESIpos): m/z=553 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.81-7.67 (m, 2H), 7.62 (d, 2H),7.54-7.37 (m, 1H), 7.37-7.18 (m, 2H), 6.93 (br s, 1H), 5.54-5.30 (m,1H), 5.21-5.06 (m, 2H), 4.28 (br s, 1H), 4.11-3.94 (m, 1H), 3.91-3.76(m, 1H), 2.29-1.98 (m, 1H), 2.29-1.98 (m, 1H), 1.87 (d, 3H), 1.70-1.57(m, 3H), 1.05-0.91 (m, 3H).

Example 495-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-[2-(methylsulfanyl)phenyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Diastereomeric Mixture)

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 138 mg, 365 μmol) in THF (3.0 ml) was cooled to 0° C. andtreated with 2-fluoropropanoyl chloride (Example 14A, 50.5 mg, 457 μmol)in 500 μl THF and N,N-diisopropylethylamine (80 μl, 460 μmol). Theresulting mixture was stirred for 1 h. After[2-(methylsulfanyl)phenyl]hydrazine (62.0 mg, 402 μmol) and were added,the reaction mixture was warmed up to room temperature and stirred for 1h, followed by 3 h at 120° C. in a sealed vial under microwaveirradiation. The crude product was purified by preparative HPLC (Method9). Lyophilisation of the product containing fractions afforded 88.5 mg(43% of th.) of the title compound as solid and as a mixture ofdiastereomers.

LC-MS (Method 8): R_(t)=2.01 min; MS (ESIpos): m/z=557 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.76 (d, 2H), 7.67-7.58 (m, 3H),7.54-7.49 (m, 1H), 7.45 (d, 1H), 7.39-7.31 (m, 1H), 6.90 (br s, 1H),5.67-5.38 (m, 1H), 5.18-5.02 (m, 2H), 4.30 (br s, 1H), 4.08-3.94 (m,1H), 3.85 (dd, 1H), 1.73-1.52 (m, 3H).

Example 505-(4-Chlorophenyl)-2-{[1-(3-chlorophenyl)-5-(difluoromethyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

To a solution of5-(4-chlorophenyl)-2-{[5-(difluoromethyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 5A, 155 mg, 0.35 mmol) in pyridine (4 ml) were added(3-chlorophenyl)boronic acid (110.5 mg, 0.707 mmol) and copper(II)acetate (128.3 mg, 0.707 mmol). The reaction mixture was stirred for 4days at room temperature, after which boronic acid (27.7 mg, 0.177 mmol)was added. After 5 additional days of stirring, the reaction mixture wasconcentrated in vacuo, then diluted with tert-butyl-methylether andquenched with aqueous HCl (0.5 M). After phase separation, the aqueousphase was extracted twice with tert-butyl-methylether. The combinedorganic phases were dried over sodium sulfate, filtered, andconcentrated in vacuo. The crude product was purified by preparativeHPLC (Method 9), and 17.4 mg (8.3% of th.) of the desired compound wasobtained.

LC-MS (Method 3): R_(t)=3.63 min; MS (ESIpos): m/z=549 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆) δ[ppm]=7.72-7.78 (m, 3H), 7.55-7.71 (m, 5H),7.35 (t, 1H), 6.90 (br. d, 1H), 5.16 (s, 2H), 4.30 (br. s., 1H), 4.01(dd, 1H), 3.86 (dd, 1H).

Example 515-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(difluoromethyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Under argon, potassium tert-butoxide (80.9 mg, 0.585 mmol) was added atroom temperature to a solution of5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 5A in WO 2011/104322-A1; 90 mg, 0.29 mmol) and a catalyticamount of potassium iodide in acetonitrile (3.3 ml). To this solutionwas added3-(Bromomethyl)-1-(2-chlorophenyl)-5-(difluoromethyl)-1H-1,2,4-triazole(Example 13A, 99.1 mg, 0.307 mmol), and the reaction mixture was stirredat reflux for 5 h. After stirring overnight at room temperature, thereaction mixture was concentrated in vacuo, and then diluted with ethylacetate and water. After phase separation, the aqueous phase wasextracted twice with ethyl acetate. The combined organic phases weredried over sodium sulfate, filtered, and concentrated in vacuo. Thecrude product was purified by preparative HPLC (Method 9), and 112.4 mg(70% of th.) of the desired compound was obtained.

LC-MS (Method 1): R_(t)=1.36 min; MS (ESIpos): m/z=549 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆) δ [ppm]=7.76 (m, 4H), 7.68 (td, 1H), 7.63 (m,2H), 7.58 (td, 1H), 7.24 (t, 1H), 6.92 (d, 1H), 5.18 (m, 2H), 4.30 (br.s., 1H), 4.01 (dd, 1H), 3.86 (dd, 1H).

Example 525-(4-Chlorophenyl)-2-{[5-(difluoromethyl)-1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

To a solution of5-(4-chlorophenyl)-2-{[5-(difluoromethyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 5A, 150 mg, 0.34 mmol) in pyridine (3.9 ml) were added(3-fluorophenyl)boronic acid (95.7 mg, 0.68 mmol) and copper(II) acetate(124.1 mg, 0.68 mmol). The reaction mixture was stirred for 4 days atroom temperature, after which boronic acid (23.9 mg, 0.171 mmol) wasadded. After 4 days of stirring, the reaction mixture was concentratedin vacuo, then diluted with tert-butyl-methylether and quenched withaqueous HCl (0.5 M). After phase separation, the aqueous phase wasextracted twice with tert-butyl-methylether. The combined organic phaseswere dried over sodium sulfate, filtered, and concentrated in vacuo. Thecrude product was purified by preparative HPLC (Method 9), and 18 mg(10% of th.) of the desired compound was obtained.

LC-MS (Method 3): R_(t)=3.42 min; MS (ESIpos): m/z=533 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=7.73-7.79 (m, 2H), 7.43-7.70 (m, 6H),7.36 (t, 1H), 6.88-6.94 (m, 1H), 5.17 (s, 2H), 4.24-4.36 (m, 1H), 4.02(dd, 1H), 3.85 (dd, 1H).

Example 535-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(1,1-difluoroethyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 151 mg, 400 μmol) in THF (3.0 ml) was cooled to 0° C. andtreated with 2,2-difluoropropanoyl chloride (Example 15A, 64.3 mg, 500μmol) in 500 μl THF and N,N-diisopropylethylamine (87 μl, 500 μmol). Theresulting mixture was stirred for 30 min After (2-chlorophenyl)hydrazinehydrochloride (1:1) (78.8 mg, 440 μmol) and N,N-diisopropylethylamine(77 μl, 440 μmol) were added, the reaction mixture was warmed up to roomtemperature and stirred for 1 h, followed by 2 h at 120° C. in a sealedvial under microwave irradiation. The crude product was purified bypreparative HPLC (Method 9). Lyophilisation of the product containingfractions afforded 148 mg (66% of th.) of the title compound as solid.

LC-MS (Method 8): R_(t)=2.11 min; MS (ESIpos): m/z=563 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.88-7.68 (m, 4H), 7.68-7.59 (m, 3H),7.59-7.45 (m, 1H), 6.90 (d, 1H), 5.16 (d, 2H), 4.39-4.20 (m, 1H),4.13-3.94 (m, 1H), 3.85 (dd, 1H), 2.05 (t, 3H).

Example 545-(4-Chlorophenyl)-2-{[1-(4-chloropyridin-3-yl)-5-(1,1-difluoroethyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 151 mg, 400 μmol) in THF (3.0 ml) was cooled to 0° C. andtreated with 2,2-difluoropropanoyl chloride (Example 15A, 64.3 mg, 500μmol) in 500 μl THF and N,N-diisopropylethylamine (87 μl, 500 μmol). Theresulting mixture was stirred for 30 min After4-chloro-3-hydrazinylpyridine hydrochloride (1:1) (79.2 mg, 440 μmol)and N,N-diisopropylethylamine (77 μl, 440 μmol) were added, the reactionmixture was warmed up to room temperature and stirred for 1 h, followedby 2 h at 120° C. in a sealed vial under microwave irradiation. Thecrude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 129 mg (57%of th.) of the title compound as solid.

LC-MS (Method 8): R_(t)=1.91 min; MS (ESIpos): m/z=564 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.92 (s, 1H), 8.79 (d, 1H), 7.91 (d,1H), 7.79-7.69 (m, 2H), 7.69-7.58 (m, 2H), 6.89 (d, 1H), 5.19 (d, 2H),4.29 (br d, 1H), 4.08-3.94 (m, 1H), 3.86 (dd, 1H), 2.09 (t, 3H).

Example 555-(4-Chlorophenyl)-2-{[1-(3-chlorophenyl)-5-(1,1-difluoroethyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 65.0 mg, 172 μmol) in THF (1.0 ml) was cooled to 0° C. andtreated with 2,2-difluoropropanoyl chloride (Example 15A, 27.6 mg, 215μmol) in 500 μl THF and N,N-diisopropylethylamine (33 μl, 190 μmol). Theresulting mixture was stirred for 30 min After (3-chlorophenyl)hydrazinehydrochloride (1:1) (33.8 mg, 189 μmol) and N,N-diisopropylethylamine(37 μl, 210 μmol) were added, the reaction mixture was warmed up to roomtemperature and stirred for 1 h, followed by 2 h at 120° C. in a sealedvial under microwave irradiation. The crude product was purified bypreparative HPLC (Method 9). Lyophilisation of the product containingfractions afforded 49.2 mg (51% of th.) of the title compound as solid.

LC-MS (Method 3): R_(t)=1.17 min; MS (ESIpos): m/z=563 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.78-7.73 (m, 2H), 7.72-7.66 (m, 2H),7.65-7.57 (m, 3H), 7.57-7.52 (m, 1H), 6.89 (d, 1H), 5.14 (s, 2H), 4.29(br d, 1H), 4.11-3.94 (m, 1H), 3.85 (dd, 1H), 2.08 (t, 3H).

Example 565-(4-Chlorophenyl)-2-{[5-(1,1-difluoroethyl)-1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 65.0 mg, 172 μmol) in THF (1.0 ml) was cooled to 0° C. andtreated with 2,2-difluoropropanoyl chloride (Example 15A, 27.6 mg, 215μmol) in 500 μl THF and N,N-diisopropylethylamine (37 μl, 210 μmol). Theresulting mixture was stirred for 30 min After (3-fluorophenyl)hydrazinehydrochloride (1:1) (30.7 mg, 189 μmol) and N,N-diisopropylethylamine(33 μl, 190 μmol) were added, the reaction mixture was warmed up to roomtemperature and stirred for 1 h, followed by 2 h at 120° C. in a sealedvial under microwave irradiation. The crude product was purified bypreparative HPLC (Method 9). Lyophilisation of the product containingfractions afforded 32.9 mg (35% of th.) of the title compound as solid.

LC-MS (Method 3): R_(t)=1.11 min; MS (ESIpos): m/z=547 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.78-7.73 (m, 2H), 7.67-7.59 (m, 3H),7.56-7.44 (m, 2H), 7.42 (d, 1H), 6.89 (br s, 1H), 5.14 (s, 2H),4.35-4.17 (m, 1H), 4.07-3.96 (m, 1H), 3.85 (dd, 1H), 2.08 (t, 3H).

Example 575-(4-Chlorophenyl)-2-({5-(1,1-difluoroethyl)-1-[4-(trifluoromethyl)pyridin-3-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 65.0 mg, 172 μmol) in THF (1.0 ml) was cooled to 0° C. andtreated with 2,2-difluoropropanoyl chloride (Example 15A, 27.6 mg, 215μmol) in 500 μl THF and N,N-diisopropylethylamine (37 μl, 210 μmol). Theresulting mixture was stirred for 30 min After3-hydrazinyl-4-(trifluoromethyl)pyridine (33.4 mg, 189 μmol) and THF(1.0 ml) were added, the reaction mixture was warmed up to roomtemperature and stirred for 1 h, followed by 2 h at 120° C. in a sealedvial under microwave irradiation. The crude product was purified bypreparative HPLC (Method 9). Lyophilisation of the product containingfractions afforded 37.8 mg (37% of th.) of the title compound as solid.

LC-MS (Method 3): R_(t)=1.08 min; MS (ESIpos): m/z=598 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.23-9.05 (m, 2H), 8.09 (d, 1H),7.81-7.68 (m, 2H), 7.68-7.53 (m, 2H), 6.88 (d, 1H), 5.31-5.00 (m, 2H),4.34-4.21 (m, 1H), 4.05-3.95 (m, 1H), 3.85 (dd, 1H), 2.09 (t, 3H).

Example 585-(4-Chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-5-(1,1-difluoroethyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 350 mg, 924 μmol) in 1,4-dioxane (10 ml) was cooled to 10°C. and treated with 2,2-difluoropropanoyl chloride (Example 15A, 148 mg,1.16 mmol) in 1 ml 1,4-dioxane and N,N-diisopropylethylamine (200 μl,1.2 mmol). The resulting mixture was stirred for 30 min A prestirredsolution of 3-chloro-2-hydrazinylpyridine (159 mg, 1.11 mmol) andanhydrous copper(II) sulfate (177 mg, 1.11 mmol) in 1,4-dioxane (10 ml)was added to the reaction mixture and was stirred overnight at roomtemperature. Water was added, the aqueous phase was extracted with ethylacetate, the combined organic phases were washed with sodium chloridesolution, dried over magnesium sulfate and evaporated in vacuo. Thecrude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 96.9 mg (19%of th.) of the title compound as solid.

LC-MS (Method 8): R_(t)=1.94 min; MS (ESIpos): m/z=564 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.63 (dd, 1H), 8.35 (dd, 1H),7.93-7.70 (m, 3H), 7.70-7.53 (m, 2H), 6.90 (d, 1H), 5.19 (d, 2H), 4.29(br d, 1H), 4.12-3.92 (m, 1H), 3.85 (dd, 1H), 2.08 (t, 3H).

Example 595-(4-Chlorophenyl)-2-({5-(1,1-difluoroethyl)-1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 350 mg, 924 μmol) in 1,4-dioxane (10 ml) was cooled to 10°C. and treated with 2,2-difluoropropanoyl chloride (Example 15A, 148 mg,1.16 mmol) in 1 ml 1,4-dioxane and N,N-diisopropylethylamine (200 μl,1.2 mmol). The resulting mixture was stirred for 30 min. A prestirredsolution of 2-hydrazinyl-3-(trifluoromethyl)pyridine4-methylbenzenesulfonate (1:1) (387 mg, 1.11 mmol),N,N-diisopropylethylamine (190 μl, 1.1 mmol) and anhydrous copper(II)sulfate (177 mg, 1.11 mmol) in 1,4-dioxane (10 ml) was added to thereaction mixture and was stirred overnight at room temperature. Waterwas added, the aqueous phase was extracted with ethyl acetate, thecombined organic phases were washed with sodium chloride solution, driedover magnesium sulfate and evaporated in vacuo. The crude product waspurified by preparative HPLC (Method 9). Lyophilisation of the productcontaining fractions afforded 12.3 mg (2% of th.) of the title compoundas solid.

LC-MS (Method 8): R_(t)=2.00 min; MS (ESIpos): m/z=598 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.95 (dd, 1H), 8.60 (dd, 1H),8.06-7.95 (m, 1H), 7.79-7.69 (m, 2H), 7.68-7.58 (m, 2H), 6.90 (d, 1H),5.27-5.09 (m, 2H), 4.28 (br d, 1H), 4.14-3.92 (m, 1H), 3.84 (dd, 1H),2.07 (t, 3H).

Example 605-(4-Chlorophenyl)-2-({5-(1,1-difluoroethyl)-1-[2-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 85.0 mg, 224 μmol) in THF (2.0 ml) was cooled to 0° C. andtreated with 2,2-difluoropropanoyl chloride (Example 15A, 36.1 mg, 281μmol) in 500 μl THF and N,N-diisopropylethylamine (49 μl, 280 μmol). Theresulting mixture was stirred for 30 min After[2-(trifluoromethyl)phenyl]hydrazine hydrochloride (1:1) (52.5 mg, 247μmol) and N,N-diisopropylethylamine (43 μl, 250 μmol) were added, thereaction mixture was warmed up to room temperature and stirred for 1 h,followed by 2 h at 120° C. in a sealed vial under microwave irradiation.The crude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 42.2 mg (32%of th.) of the title compound as solid.

LC-MS (Method 8): R_(t)=2.12 min; MS (ESIpos): m/z=597 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.99 (dd, 1H), 7.94-7.81 (m, 2H),7.79 (d, 1H), 7.76-7.70 (m, 2H), 7.70-7.55 (m, 2H), 6.88 (d, 1H),5.26-5.08 (m, 2H), 4.38-4.22 (m, 1H), 4.09-3.96 (m, 1H), 3.85 (dd, 1H),2.05 (t, 3H).

Example 615-(4-Chlorophenyl)-2-({5-(1,1-difluoroethyl)-1-[2-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 85.0 mg, 224 μmol) in THF (2.0 ml) was cooled to 0° C. andtreated with 2,2-difluoropropanoyl chloride (Example 15A, 36.1 mg, 281μmol) in 500 μl THF and N,N-diisopropylethylamine (49 μl, 280 μmol). Theresulting mixture was stirred for 30 min After[2-(trifluoromethoxy)phenyl]hydrazine hydrochloride (1:1) (56.4 mg, 247μmol) and N,N-diisopropylethylamine (43 μl, 250 μmol) were added, thereaction mixture was warmed up to room temperature and stirred for 1 h,followed by 2 h at 120° C. in a sealed vial under microwave irradiation.The crude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 29.0 mg (21%of th.) of the title compound as solid.

LC-MS (Method 8): R_(t)=2.16 min; MS (ESIpos): m/z=613 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.81-7.68 (m, 4H), 7.68-7.49 (m, 4H),6.92-6.84 (m, 1H), 5.15 (d, 2H), 4.35-4.21 (m, 1H), 4.06-3.95 (m, 1H),3.90-3.80 (m, 1H), 2.06 (t, 3H).

Example 625-(4-Chlorophenyl)-2-{[5-(1,1-difluoroethyl)-1-(2-ethylphenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 85.0 mg, 224 μmol) in THF (2.0 ml) was cooled to 0° C. andtreated with 2,2-difluoropropanoyl chloride (Example 15A, 36.1 mg, 281μmol) in 500 μl THF and N,N-diisopropylethylamine (49 μl, 280 μmol). Theresulting mixture was stirred for 30 min After (2-ethylphenyl)hydrazinehydrochloride (1:1) (42.6 mg, 247 μmol) and N,N-diisopropylethylamine(43 μl, 250 μmol) were added, the reaction mixture was warmed up to roomtemperature and stirred for 1 h, followed by 2 h at 120° C. in a sealedvial under microwave irradiation. The crude product was purified bypreparative HPLC (Method 9). Lyophilisation of the product containingfractions afforded 43.6 mg (35% of th.) of the title compound as solid.

LC-MS (Method 8): R_(t)=2.19 min; MS (ESIpos): m/z=557 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.77-7.68 (m, 2H), 7.68-7.58 (m, 2H),7.58-7.50 (m, 1H), 7.50-7.43 (m, 1H), 7.43-7.33 (m, 2H), 6.88 (d, 1H),5.15 (d, 2H), 4.35-4.18 (m, 1H), 4.08-3.95 (m, 1H), 3.92-3.79 (m, 1H),2.22 (q, 2H), 2.04 (t, 3H), 0.99 (t, 3H).

Example 635-(4-Chlorophenyl)-2-({5-(1,1-difluoroethyl)-1-[2-(difluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 85.0 mg, 224 μmol) in THF (2.0 ml) was cooled to 0° C. andtreated with 2,2-difluoropropanoyl chloride (Example 15A, 36.1 mg, 281μmol) in 500 μl THF and N,N-diisopropylethylamine (49 μl, 280 μmol). Theresulting mixture was stirred for 30 min After[2-(difluoromethoxy)phenyl]hydrazine (43.0 mg, 247 μmol) andN,N-diisopropylethylamine (49 μl, 280 μmol) were added, the reactionmixture was warmed up to room temperature and stirred for 1 h, followedby 2 h at 120° C. in a sealed vial under microwave irradiation. Thecrude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 25.6 mg (19%of th.) of the title compound as solid.

LC-MS (Method 8): R_(t)=2.05 min; MS (ESIpos): m/z=595 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.75 (d, 2H), 7.71-7.64 (m, 2H),7.64-7.57 (m, 2H), 7.43 (br d, 2H), 7.24 (s, 1H), 6.89 (d, 1H), 5.15 (d,2H), 4.35-4.22 (m, 1H), 4.07-3.93 (m, 1H), 3.85 (dd, 1H), 2.04 (t, 3H).

Example 645-(4-Chlorophenyl)-2-{[5-(1,1-difluoroethyl)-1-(2-methylphenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 85.0 mg, 224 μmol) in THF (2.0 ml) was cooled to 0° C. andtreated with 2,2-difluoropropanoyl chloride (Example 15A, 36.1 mg, 281μmol) in 500 μl THF and N,N-diisopropylethylamine (49 μl, 280 μmol). Theresulting mixture was stirred for 30 min After (2-methylphenyl)hydrazinehydrochloride (1:1) (39.2 mg, 247 μmol) and N,N-diisopropylethylamine(43 μl, 250 μmol) were added, the reaction mixture was warmed up to roomtemperature and stirred for 1 h, followed by 2 h at 120° C. in a sealedvial under microwave irradiation. The crude product was purified bypreparative HPLC (Method 9). Lyophilisation of the product containingfractions afforded 44.4 mg (36% of th.) of the title compound as solid.

LC-MS (Method 8): R_(t)=2.10 min; MS (ESIpos): m/z=543 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.80-7.69 (m, 2H), 7.69-7.60 (m, 2H),7.53-7.46 (m, 1H), 7.46-7.34 (m, 3H), 6.89 (d, 1H), 5.15 (d, 2H),4.36-4.18 (m, 1H), 4.11-3.96 (m, 1H), 3.85 (dd, 1H), 2.03 (t, 3H), 1.95(s, 3H).

Example 655-(4-Chlorophenyl)-2-{[5-(1,1-difluoroethyl)-1-(2-nitrophenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 65.0 mg, 172 μmol) in THF (2.0 ml) was cooled to 0° C. andtreated with 2,2-difluoropropanoyl chloride (Example 15A, 27.6 mg, 215μmol) in 500 μl THF and N,N-diisopropylethylamine (37 μl, 210 μmol). Theresulting mixture was stirred for 30 min After (2-nitrophenyl)hydrazine(28.9 mg, 189 μmol) was added, the reaction mixture was warmed up toroom temperature and stirred for 1 h, followed by 2 h at 120° C. in asealed vial under microwave irradiation. The crude product was purifiedby preparative HPLC (Method 9). Lyophilisation of the product containingfractions afforded 14.9 mg (15% of th.) of the title compound as solid.

LC-MS (Method 3): R_(t)=1.06 min; MS (ESIpos): m/z=574 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.33-8.26 (m, 1H), 7.91 (br d, 3H),7.80-7.69 (m, 2H), 7.63 (d, 2H), 6.89 (d, 1H), 5.15 (d, 2H), 4.37-4.22(m, 1H), 4.09-3.96 (m, 1H), 3.91-3.78 (m, 1H), 2.07 (t, 3H).

Example 662-[3-({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-5-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl]benzenesulfonamide

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 65.0 mg, 172 μmol) in THF (1.5 ml) was cooled to 0° C. andtreated with 2,2-difluoropropanoyl chloride (Example 15A, 27.6 mg, 215μmol) in 500 μl THF and N,N-diisopropylethylamine (37 μl, 210 μmol). Theresulting mixture was stirred for 30 min. After2-hydrazinylbenzenesulfonamide (35.3 mg, 189 μmol) was added, thereaction mixture was warmed up to room temperature and stirred for 1 h,followed by 2 h at 120° C. in a sealed vial under microwave irradiation.The crude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 59.1 mg (52%of th.) of the title compound as solid.

LC-MS (Method 3): R_(t)=3.04 min; MS (ESIpos): m/z=608 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.12-8.00 (m, 1H), 7.84-7.78 (m, 2H),7.78-7.72 (m, 2H), 7.72-7.67 (m, 1H), 7.62 (d, 2H), 7.14 (s, 2H), 6.89(br d, 1H), 5.18 (d, 2H), 4.36-4.19 (m, 1H), 3.97 (br d, 1H), 3.91-3.77(m, 1H), 1.99 (t, 3H).

Example 675-(4-Chlorophenyl)-2-{[5-(1,1-difluoroethyl)-1-(2-ethoxyphenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 65.0 mg, 172 μmol) in THF (1.5 ml) was cooled to 0° C. andtreated with 2,2-difluoropropanoyl chloride (Example 15A, 27.6 mg, 215μmol) in 500 μl THF and N,N-diisopropylethylamine (33 μl, 190 μmol). Theresulting mixture was stirred for 30 min After (2-ethoxyphenyl)hydrazinehydrochloride (1:1) (35.6 mg, 189 μmol) and N,N-diisopropylethylamine(33 μl, 190 μmol) were added, the reaction mixture was warmed up to roomtemperature and stirred for 1 h, followed by 2 h at 120° C. in a sealedvial under microwave irradiation. The crude product was purified bypreparative HPLC (Method 9). Lyophilisation of the product containingfractions afforded 39.8 mg (40% of th.) of the title compound as solid.

LC-MS (Method 3): R_(t)=1.11 min; MS (ESIpos): m/z=573 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.79-7.72 (m, 2H), 7.66-7.59 (m, 2H),7.53 (ddd, 1H), 7.41 (dd, 1H), 7.22 (dd, 1H), 7.06 (td, 1H), 6.89 (d,1H), 5.12 (d, 2H), 4.35-4.23 (m, 1H), 4.08-3.97 (m, 3H), 3.85 (dd, 1H),1.99 (t, 3H), 1.11 (t, 3H).

Example 685-(4-Chlorophenyl)-2-{[1-(2,6-dichlorophenyl)-5-(1,1-difluoroethyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 65.0 mg, 172 μmol) in THF (2.0 ml) was cooled to 0° C. andtreated with 2,2-difluoropropanoyl chloride (Example 15A, 27.6 mg, 215μmol) in 500 μl THF and N,N-diisopropylethylamine (37 μl, 210 μmol). Theresulting mixture was stirred for 30 min After(2,6-dichlorophenyl)hydrazine hydrochloride (1:1) (40.3 mg, 189 μmol)and N,N-diisopropylethylamine (37 μl, 210 μmol) were added, the reactionmixture was warmed up to room temperature and stirred for 1 h, followedby 2 h at 120° C. in a sealed vial under microwave irradiation. Thecrude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 57.0 mg (56%of th.) of the title compound as solid.

LC-MS (Method 8): R_(t)=2.15 min; MS (ESIpos): m/z=597 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.79-7.72 (m, 4H), 7.70 (d, 1H), 7.63(d, 2H), 6.89 (d, 1H), 5.28-5.09 (m, 2H), 4.29 (br d, 1H), 3.99 (d, 1H),3.90-3.82 (m, 1H), 2.07 (t, 3H).

Example 692-{[1-(2-Chloro-6-fluorophenyl)-5-(1,1-difluoroethyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 65.0 mg, 172 μmol) in THF (2.0 ml) was cooled to 0° C. andtreated with 2,2-difluoropropanoyl chloride (Example 15A, 27.6 mg, 215μmol) in 500 μl THF and N,N-diisopropylethylamine (33 μl, 190 μmol). Theresulting mixture was stirred for 30 min After(2-chloro-6-fluorophenyl)hydrazine hydrochloride (1:1) (37.2 mg, 189μmol) and N,N-diisopropylethylamine (33 μl, 190 μmol) were added, thereaction mixture was warmed up to room temperature and stirred for 1 h,followed by 2 h at 120° C. in a sealed vial under microwave irradiation.The crude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 61.3 mg (61%of th.) of the title compound as solid.

LC-MS (Method 8): R_(t)=2.10 min; MS (ESIpos): m/z=581 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.81-7.70 (m, 3H), 7.68-7.55 (m, 4H),6.89 (d, 1H), 5.27-5.10 (m, 2H), 4.29 (br d, 1H), 4.10-3.93 (m, 1H),3.93-3.77 (m, 1H), 2.08 (t, 3H).

Example 705-(4-Chlorophenyl)-2-{[5-(1,1-difluoroethyl)-1-(2,6-difluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 65.0 mg, 172 μmol) in THF (2.0 ml) was cooled to 0° C. andtreated with 2,2-difluoropropanoyl chloride (Example 15A, 27.6 mg, 215μmol) in 500 μl THF and N,N-diisopropylethylamine (33 μl, 190 μmol). Theresulting mixture was stirred for 30 min After(2,6-difluorophenyl)hydrazine hydrochloride (1:1) (34.1 mg, 189 μmol)and N,N-diisopropylethylamine (33 μl, 190 μmol) were added, the reactionmixture was warmed up to room temperature and stirred for 1 h, followedby 2 h at 120° C. in a sealed vial under microwave irradiation. Thecrude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 55.1 mg (57%of th.) of the title compound as solid.

LC-MS (Method 8): R_(t)=2.05 min; MS (ESIpos): m/z=565 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.83-7.71 (m, 3H), 7.65-7.59 (m, 2H),7.46 (t, 2H), 6.89 (br d, 1H), 5.19 (d, 2H), 4.28 (br s, 1H), 4.05-3.95(m, 1H), 3.85 (dd, 1H), 2.10 (t, 3H).

Example 715-(4-Chlorophenyl)-2-{[5-(1,1-difluoroethyl)-1-(2,6-dimethylphenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 65.0 mg, 172 μmol) in THF (2.0 ml) was cooled to 0° C. andtreated with 2,2-difluoropropanoyl chloride (Example 15A, 27.6 mg, 215μmol) in 500 μl THF and N,N-diisopropylethylamine (37 μl, 210 μmol). Theresulting mixture was stirred for 30 min After(2,6-dimethylphenyl)hydrazine hydrochloride (1:1) (32.6 mg, 189 μmol)and N,N-diisopropylethylamine (37 μl, 210 μmol) were added, the reactionmixture was warmed up to room temperature and stirred for 1 h, followedby 2 h at 120° C. in a sealed vial under microwave irradiation. Thecrude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 37.4 mg (39%of th.) of the title compound as solid.

LC-MS (Method 8): R_(t)=2.19 min; MS (ESIpos): m/z=557 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.78-7.69 (m, 2H), 7.69-7.58 (m, 2H),7.45-7.32 (m, 1H), 7.25 (d, 2H), 6.89 (s, 1H), 5.26-5.03 (m, 2H), 4.28(br s, 1H), 4.07-3.92 (m, 1H), 3.92-3.73 (m, 1H), 2.06 (t, 3H), 1.90 (s,6H).

Example 725-(4-Chlorophenyl)-2-({5-(1,1-difluoroethyl)-1-[2-(propan-2-yl)phenyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 65.0 mg, 172 μmol) in THF (2.0 ml) was cooled to 0° C. andtreated with 2,2-difluoropropanoyl chloride (27.6 mg, 215 μmol) in 500μl THF and N,N-diisopropylethylamine (37 μl, 210 μmol). The resultingmixture was stirred for 30 min After [2-(propan-2-yl)phenyl]hydrazinehydrochloride (1:1) (35.2 mg, 189 μmol) and N,N-diisopropylethylamine(37 μl, 210 μmol) were added, the reaction mixture was warmed up to roomtemperature and stirred for 1 h, followed by 2 h at 120° C. in a sealedvial under microwave irradiation. The crude product was purified bypreparative HPLC (Method 9). Lyophilisation of the product containingfractions afforded 51.4 mg (52% of th.) of the title compound as solid.

LC-MS (Method 3): R_(t)=1.27 min; MS (ESIpos): m/z=571 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.73 (d, 2H), 7.65-7.59 (m, 2H),7.59-7.48 (m, 2H), 7.41-7.30 (m, 2H), 6.88 (d, 1H), 5.23-5.09 (m, 2H),4.40-4.13 (m, 1H), 4.06-3.93 (m, 1H), 3.93-3.79 (m, 1H), 2.30-2.20 (m,1H), 2.04 (t, 3H), 1.05 (br d, 6H).

Example 735-(4-Chlorophenyl)-2-{[5-(1,1-difluoroethyl)-1-(2-ethyl-6-methylphenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 65.0 mg, 172 μmol) in THF (2.0 ml) was cooled to 0° C. andtreated with 2,2-difluoropropanoyl chloride (Example 15A, 27.6 mg, 215μmol) in 500 μl THF and N,N-diisopropylethylamine (37 μl, 210 μmol). Theresulting mixture was stirred for 30 min After(2-ethyl-6-methylphenyl)hydrazine hydrochloride (1:1) (35.2 mg, 189μmol) and N,N-diisopropylethylamine (37 μl, 210 μmol) were added, thereaction mixture was warmed up to room temperature and stirred for 1 h,followed by 2 h at 120° C. in a sealed vial under microwave irradiation.The crude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 39.0 mg (40%of th.) of the title compound as solid.

LC-MS (Method 3): R_(t)=1.27 min; MS (ESIpos): m/z=571 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.78-7.68 (m, 2H), 7.68-7.58 (m, 2H),7.47-7.37 (m, 1H), 7.26 (dd, 2H), 6.89 (d, 1H), 5.22-5.08 (m, 2H), 4.28(br d, 1H), 4.14-3.92 (m, 1H), 3.92-3.75 (m, 1H), 2.22 (s, 1H), 2.05 (s,4H), 1.88 (s, 3H), 1.00 (td, 3H).

Example 745-(4-Chlorophenyl)-2-({5-(1,1-difluoroethyl)-1-[2-(methylsulfanyl)phenyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 65.0 mg, 172 μmol) in THF (2.0 ml) was cooled to 0° C. andtreated with 2,2-difluoropropanoyl chloride (Example 15A, 27.6 mg, 215μmol) in 500 μl THF and N,N-diisopropylethylamine (37 μl, 210 μmol). Theresulting mixture was stirred for 30 min After[2-(methylsulfanyl)phenyl]hydrazine (29.1 mg, 189 μmol) andN,N-diisopropylethylamine (37 μl, 210 μmol) were added, the reactionmixture was warmed up to room temperature and stirred for 1 h, followedby 2 h at 120° C. in a sealed vial under microwave irradiation. Thecrude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions 45.5 mg (46% of th.)of the title compound as solid.

LC-MS (Method 8): R_(t)=2.08 min; MS (ESIpos): m/z=575 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.76 (d, 2H), 7.69-7.54 (m, 3H),7.54-7.41 (m, 1H), 7.39-7.18 (m, 1H), 6.90 (d, 1H), 5.27-5.02 (m, 2H),4.29 (br d, 1H), 4.08-3.91 (m, 1H), 3.85 (dd, 1H), 2.40 (s, 3H), 2.01(t, 3H).

Example 755-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[difluoro(1-hydroxycyclopentyl)methyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 379 mg, 1.00 mmol) in THF (7.6 ml) was cooled to 0° C. andtreated with difluoro(1-hydroxycyclopentyl)acetyl chloride (Example 16A,238 mg, 1.20 mmol) in 500 μl THF and N,N-diisopropylethylamine (700 μl,4.0 mmol). The resulting mixture was stirred for 30 min After(2-chlorophenyl)hydrazine hydrochloride (1:1) (203 mg, 97% purity, 1.10mmol) and N,N-diisopropylethylamine (700 μl, 4.0 mmol) were added, thereaction mixture was warmed up to room temperature and stirred for 1 h,followed by 2 h at 120° C. in a sealed vial under microwave irradiation.The crude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 163 mg (26%of th.) of the title compound as solid.

LC-MS (Methode 1): R_(t)=1.48 min; MS (ESIpos): m/z=633 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.78-7.71 (m, 2H), 7.71-7.65 (m, 1H),7.65-7.61 (m, 2H), 7.61-7.56 (m, 1H), 7.61-7.56 (m, 1H), 7.53-7.48 (m,1H), 6.88 (br d, 1H), 5.36 (s, 1H), 5.16 (d, 2H), 4.28 (br d, 1H),4.06-3.95 (m, 1H), 3.85 (dd, 1H), 2.03 (br s, 1H), 1.90 (br s, 1H),1.75-1.50 (m, 6H).

Example 762-{[5-(2-Amino-1,1-difluoroethyl)-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-oneas formic acid salt

2-{2-[1-(2-chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]-2,2-difluoroethyl}-1H-isoindole-1,3(2H)-dione(Example 20A, 100 mg, 141 μmol) and hydrazine hydrate (34 μl, 710 μmol)were dissolved in ethanol (6.0 ml, 100 mmol) and stirred for 1 h at roomtemperature. The crude product was purified by preparative HPLC (Method9). Lyophilisation of the product containing fractions afforded 69.0 mg(77% of th.) of the title compound as solid.

LC-MS (Method 1): R_(t)=1.02 min; MS (ESIpos): m/z=578 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.14 (s, 1H), 7.79-7.60 (m, 8H), 7.55(dd, 1H), 6.90 (br s, 1H), 5.17 (d, 2H), 4.29 (br s, 1H), 4.01 (dd, 1H),3.85 (dd, 1H), 3.28 (br d, 2H).

Example 775-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[difluoro(tetrahydro-2H-pyran-4-yl)methyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 202 mg, 533 μmol) in THF (4.0 ml) was cooled to 0° C. andtreated with difluoro(tetrahydro-2H-pyran-4-yl)acetyl chloride (Example19A, 132 mg, 666 μmol) in 500 μl THF and N,N-diisopropylethylamine (230μl, 1.3 mmol). The resulting mixture was stirred for 30 min After(2-chlorophenyl)hydrazine hydrochloride (1:1) (105 mg, 586 μmol) andN,N-diisopropylethylamine (230 μl, 1.3 mmol) were added, the reactionmixture was warmed up to room temperature and stirred for 1 h, followedby 2 h at 120° C. in a sealed vial under microwave irradiation. Thecrude product was purified by preparative HPLC (Method 9).Lyophilisation of the product containing fractions afforded 250 mg (74%of th.) of the title compound as solid.

LC-MS (Method 1): R_(t)=1.45 min; MS (ESIpos): m/z=633 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.76-7.72 (m, 3H), 7.69 (td, 1H),7.66-7.61 (m, 3H), 7.58-7.51 (m, 1H), 6.88 (d, 1H), 5.25-5.10 (m, 2H),4.39-4.20 (m, 1H), 4.07-3.96 (m, 1H), 3.94-3.78 (m, 3H), 3.30-3.22 (m,2H), 2.72-2.58 (m, 1H), 1.59 (br s, 2H), 1.41 (qd, 2H).

Example 785-(4-Chlorophenyl)-2-{[1-(3-fluorophenyl)-5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Under argon, potassium tert-butoxide (81.2 mg, 0.588 mmol) was added atroom temperature to a solution of5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 5A in WO 2011/104322-A1; 90.4 mg, 0.29 mmol) and a catalyticamount of potassium iodide in acetonitrile (3.3 ml). To this solutionwas added3-(bromomethyl)-1-(3-fluorophenyl)-5-(trifluoromethyl)-1H-1,2,4-triazole(Example 8A, 100 mg, 0.309 mmol), and the reaction mixture was stirredat reflux for 5 h. After an overnight stirring at room temperature, thereaction mixture was concentrated in vacuo, and then diluted with ethylacetate and water. After phase separation, the aqueous phase wasextracted twice with ethyl acetate. The combined organic phases weredried over sodium sulfate, filtered, and concentrated in vacuo. Thecrude was purified by preparative HPLC (Method 9). Lyophilisation of theproduct containing fractions afforded 126 mg (78% of th.) of the titlecompound as solid.

LC-MS (Method 2): R_(t)=1.22 min; MS (ESIpos): m/z=551 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]=7.73-7.79 (m, 2H), 7.60-7.71 (m, 4H),7.48-7.57 (m, 2H), 6.89 (br. d, 1H), 5.21 (s, 2H), 4.30 (br. s., 1H),4.02 (dd, 1H), 3.86 (dd, 1H).

Example 795-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Under argon, potassium tert-butoxide (80.9 mg, 0.585 mmol) was added atroom temperature to a solution of5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 5A in WO 2011/104322-A1; 90 mg, 0.29 mmol) and a catalyticamount of potassium iodide in acetonitrile (3.3 ml). To this solutionwas added3-(Bromomethyl)-1-(2-chlorophenyl)-5-(trifluoromethyl)-1H-1,2,4-triazole(Example 11A, 104.6 mg, 0.307 mmol), and the reaction mixture wasstirred at reflux for 5 h. After an overnight stirring at roomtemperature, the reaction mixture was concentrated in vacuo, and thendiluted with ethyl acetate and water. After phase separation, theaqueous phase was extracted twice with ethyl acetate. The combinedorganic phases were dried over sodium sulfate, filtered, andconcentrated in vacuo. The crude was purified by preparative HPLC(Method 9). Lyophilisation of the product containing fractions afforded115 mg (70% of th.) of the title compound as solid.

LC-MS [Methode 1]: R_(t)=1.46 min; MS (ESIpos): m/z=567 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ[ppm]=7.87 (dd, 1H), 7.68-7.82 (m, 4H),7.58-7.66 (m, 3H), 6.89 (d, 1H), 5.19-5.29 (m, 2H), 4.29 (br. s., 1H),4.02 (dd, 1H), 3.86 (dd, 1H).

EXPERIMENTAL SECTION—BIOLOGICAL ASSAYS Abbreviations and Acronyms:

Acc. No. accession numberAVP arginine vasopressinBmax maximal ligand binding capacityBSA bovine serum albumincAMP cyclic adenosine monophosphateCat. No. catalogue numbercDNA complementary deoxyribonucleic acidCHO chinese hamster ovaryCRE cAMP response elementCt cycle thresholdDMEM/F12 Dulbecco's modified Eagle's medium/Ham's F12 medium (1:1)DNA deoxyribonucleic acidDMSO dimethylsulfoxideDTT dithiothreitolEC₅₀ half-maximal effective concentrationEDTA ethylenediamine-tetraacetic acidFAM carboxyfluorescein succinimidyl esterf.c. final concentrationFCS fetal calf serumHEPES 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acidIC₅₀ half-maximal inhibitory concentrationK_(d) dissociation constantK_(i) dissociation constant of an inhibitormRNA messenger ribonucleic acidPBS phosphate buffered salinePEG polyethylene glycolp.o. per os, peroralRNA ribonucleic acidRTPCR real-time polymerase chain reactionSPA scintillation proximity assayTAMRA carboxytetramethylrhodamineTRIS; Tris 2-amino-2-hydroxymethylpropane-1,3-diol

Demonstration of the activity of the compounds of the present inventionmay be accomplished through in vitro, ex vivo, and in vivo assays thatare well known in the art. For example, to demonstrate the activity ofthe compounds of the present invention, the following assays may beused.

B-1. Cellular In Vitro Assay for Determining Vasopressin ReceptorActivity

The identification of agonists and antagonists of the V1a and V2vasopressin receptors from humans, rats and dogs as well as thequantification of the activity of the compounds of the invention iscarried out using recombinant cell lines. These cell lines originallyderive from a hamster's ovary epithelial cell (Chinese Hamster Ovary,CHO K1, ATCC: American Type Culture Collection, Manassas, Va. 20108,USA). The test cell lines constitutively express the human, rat or dogV1a or V2 receptors. In case of the G_(αq)-coupled V1a receptors, cellsare also stably transfected with a modified form of thecalcium-sensitive photoproteins aequorin (human and rat V1a) or obelin(dog V1a), which, after reconstitution with the cofactor coelenterazine,emit light when there are increases in free calcium concentrations[Rizzuto R, Simpson A W, Brini M, Pozzan T, Nature 358, 325-327 (1992);Illarionov B A, Bondar V S, Illarionova V A, Vysotski E S, Gene 153 (2),273-274 (1995)]. The resulting vasopressin receptor cells react tostimulation of the recombinantly expressed V1a receptors byintracellular release of calcium ions, which can be quantified by theresulting photoprotein luminescence. The G_(s)-coupled V2 receptors arestably transfected into cell lines expressing the gene for fireflyluciferase under control of a CRE-responsible promoter. Activation of V2receptors induces the activation of the CRE-responsive promoter via cAMPincrease, thereby inducing the expression of firefly luciferase. Thelight emitted by photoproteins of V1a cell lines as well as the lightemitted by firefly luciferase of V2 cell lines corresponds to theactivation or inhibition of the respective vasopressin receptor. Thebioluminescence of the cell lines is detected using a suitableluminometer [Milligan G, Marshall F, Rees S, Trends in PharmacologicalSciences 17, 235-237 (1996)].

Test Procedure: Vasopressin V1a Receptor Cell Lines:

On the day before the assay, the cells are plated out in culture medium(DMEM/F12, 2% FCS, 2 mM glutamine, 10 mM HEPES, 5 μg/ml coelenterazine)in 384-well microtiter plates and kept in a cell incubator (96%humidity, 5% v/v CO₂, 37° C.). On the day of the assay, test compoundsin various concentrations are placed for 10 minutes in the wells of themicrotiter plate before the agonist [Arg⁸]-vasopressin at EC₅₀concentration is added. The resulting light signal is measuredimmediately in a luminometer.

Vasopressin V2 Receptor Cell Lines:

On the day before the assay, the cells are plated out in culture medium(DMEM/F12, 2% FCS, 2 mM glutamine, 10 mM HEPES) in 384-well microtiterplates and kept in a cell incubator (96% humidity, 5% v/v CO₂, 37° C.).On the day of the assay, test compounds in various concentrations andthe agonist [Arg⁸]-vasopressin at EC₅₀ concentration are added togetherto the wells, and plates are incubated for 3 hours in a cell incubator.Upon addition of the cell lysis reagent Triton™ and the substrateluciferin, luminescence of firefly luciferase is measured in aluminometer.

Table 1A below lists individual IC₅₀ values for the compounds of theinvention (including racemic mixtures as well as separated enantiomers)that were obtained from cell lines transfected with the human V1a or V2receptor:

TABLE 1A Example IC₅₀hV1a IC₅₀hV2 ratio IC₅₀ No. [μM] [μM] hV2/hV1a  10.00035 0.00070 2.0  2 0.00036 0.00134 3.8  3 0.00090 0.00093 1.0  40.00205 0.01850 9.0  5 0.00695 0.07475 10.8  6 0.00048 0.00237 5.0  70.00113 0.01250 11.1  8 0.00125 0.01975 15.8  9 0.00100 0.00705 7.1 110.01350 0.07375 5.5 12 0.00380 0.02250 5.9 14 0.00970 0.00173 0.2 150.01250 0.00785 0.6 16 0.01600 0.00058 0.0 17 0.00925 0.00025 0.0 180.06000 0.00385 0.1 19 0.00285 0.01475 5.2 20 0.00135 0.00595 4.4 210.00155 0.01250 8.1 22 0.00390 0.01350 3.5 23 0.00375 0.03300 8.8 240.00110 0.00465 4.2 25 0.00270 0.01700 6.3 26 0.00300 0.01750 5.8 270.00175 0.00980 5.6 28 0.00185 0.00076 0.4 29 0.00091 0.00037 0.4 300.00185 0.00190 1.0 31 0.00175 0.00458 2.6 32 0.00240 0.00890 3.7 330.00215 0.00180 0.8 34 0.00071 0.00084 1.2 35 0.00036 0.00017 0.5 360.00065 0.00098 1.5 37 0.00335 0.01000 3.0 38 0.08200 0.16500 2.0 390.02220 0.26050 11.7 40 0.02850 0.42000 14.7 41 0.08475 0.29250 3.5 420.00190 0.00495 2.6 43 0.00205 0.00310 1.5 44 0.00104 0.00293 2.8 450.00220 0.00297 1.3 46 0.00320 0.00174 0.5 47 0.03000 0.03500 1.2 480.03050 0.00490 0.2 49 0.00085 0.00045 0.5 50 0.03600 0.00259 0.1 510.00147 0.00220 1.5 52 0.01080 0.00592 0.5 53 0.00040 0.00116 2.9 540.00093 0.01125 12.2 55 0.06000 0.00523 0.1 56 0.01550 0.00525 0.3 570.00200 0.02450 12.3 58 0.00100 0.00340 3.4 59 0.00470 0.02675 5.7 600.00173 0.01160 6.7 61 0.00415 0.04450 10.7 62 0.00220 0.00225 1.0 630.00210 0.00695 3.3 64 0.00106 0.00170 1.6 65 0.00305 0.01140 3.7 660.05800 0.34000 5.9 67 0.00180 0.00785 4.4 68 0.00330 0.00423 1.3 690.00295 0.00690 2.3 70 0.00175 0.00227 1.3 71 0.00530 0.00427 0.8 720.03100 0.03467 1.1 73 0.04100 0.01190 0.3 74 0.00140 0.00098 0.7 750.00085 0.00540 6.4 76 0.00091 0.00315 3.5 77 0.00140 0.00703 5.0 780.04960 0.00475 0.1 79 0.00078 0.00258 3.3

B-2. Radioactive Binding Assay

IC₅₀ and K, values can be determined in radioactive binding assays usingmembrane fractions of recombinant human embryonic kidney cell line 293(HEK293) or CHO-K1 cell lines expressing the respective humanvasopressin V1a and V2 receptors.

Human recombinant vasopressin V1a receptors expressed in HEK293 cellsare used in 50 mM Tris-HCl buffer, pH 7.4, 5 mM MgCl₂, 0.1% BSA usingstandard techniques. Aliquots of prepared membranes are incubated withtest compounds in various concentrations in duplicates and 0.03 nM[¹²⁵I]Phenylacetyl-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH₂ for 120minutes at 25° C. Nonspecific binding is estimated in the presence of 1μM [Arg⁸]Vasopressin. Receptors are filtered and washed, the filters arethen counted to determine[¹²⁵I]Phenylacetyl-D-Tyr(Me)-Phe-Gln-Asn-ArgPro-Arg-Tyr-NH₂ specificallybound.

CHO-K1 cells stably transfected with a plasmid encoding humanvasopressin V2 receptor are used to prepare membranes in 50 mM Tris-HClbuffer, pH 7.4, 10 mM MgCl₂, 0.1% BSA using standard techniques.Aliquots of prepared membrane are incubated with test compounds invarious concentrations in duplicates and 4 nM [³H](Arg⁸)-Vasopressin for120 minutes at 25° C. Nonspecific binding is estimated in the presenceof 1 mM (Arg⁸)-vasopressin. Membranes are filtered and washed 3 timesand the filters are counted to determine [³H](Arg₈)-Vasopressinspecifically bound.

IC₅₀ values are determined by a non-linear, least squares regressionanalysis using MathIQ™ (ID Business Solutions Ltd., UK). The inhibitionconstant K, is calculated using the equation of Cheng and Prusoff(Cheng, Y., Prusoff, W. H., Biochem. Pharmacol. 22:3099-3108, 1973).

B-3. Cellular In Vitro Assay for Detecting the Action of Vasopressin V1aReceptor Antagonists on the Regulation of Pro-Fibrotic Genes

The cell line H9C2 (American Type Culture Collection ATCC No. CRL-1446),described as a cardiomyocyte type isolated from rat cardiac tissue,endogenously expresses the vasopressin V1a receptor AVPR1A in high copynumber, whereas AVPR2 expression cannot be detected. Likewise, the cellline NRK49F (ATCC No. CRL1570) isolated from rat kidney tissue, showssimilar expression pattern of high AVPR1A mRNA expression anddiminishing AVPR2 expression. For cell assays detecting the inhibitionof AVPR1A receptor-dependent regulation of gene expression by receptorantagonists, the procedure is as follows:

H9C2 cells or NRK49F cells are seeded in 6-well microtiter plates forcell culture at a cell density of 50 000 cells/well in 2.0 ml ofOpti-MEM medium (Invitrogen Corp., Carlsbad, Calif., USA, Cat. No.11058-021) and held in a cell incubator (96% humidity, 8% v/v CO₂, 37°C.). After 24 hours, sets of three wells (triplicate) are charged withvehicle solution (negative control) and vasopressin solution([Arg8]-vasopressin acetate, Sigma, Cat. No. V9879), or test compound(dissolved in vehicle: water with 20% v/v ethanol) and vasopressinsolution. In the cell culture, the final vasopressin concentration is 1nM. The test compound solution is added to the cell culture in smallvolumes, so that a final concentration of 0.03% of ethanol in the cellassay is not exceeded. After an incubation time of 5 hours, the culturesupernatant is drawn off under suction, the adherent cells are lysed in350 μl of RLT buffer (Qiagen, Cat. No. 79216), and the RNA is isolatedfrom the lysate using the RNeasy kit (Qiagen, Cat. No. 74104). This isfollowed by DNAse digestion (Invitrogen, Cat. No. 18068-015), cDNAsynthesis (Promaga, ImProm-II Reverse Transcription System, Cat. No.A3800) and Reverse Transcription Polymerase Chain Reaction (RTPCR) (pPCRMasterMix RT-QP2X-03-075, Eurogentec, Seraing, Belgium). All procedurestake place in accordance with the working protocols of the testreagents' manufacturers. The primer sets for the RTPCR are selected onthe basis of the mRNA gene sequences (NCBI GenBank Entrez NucleotideData Base) using the Primer3Plus program with 6-FAM TAMRA-labelledprobes. The RTPCR for determining the relative mRNA expression in thecells of the various assay batches is carried out using the AppliedBiosystems ABI Prism 7700 Sequence Detector in 384-well microtiter plateformat in accordance with the instrument operating instructions. Therelative gene expression is represented by the delta-delta Ct value[Applied Biosystems, User Bulletin No. 2 ABI Prism 7700 SDS, Dec. 11,1997 (updated 10/2001)] with reference to the level of expression of theribosomal protein L-32 gene (GenBank Acc. No. NM_013226) and thethreshold Ct value of Ct=35.

B-4. Inhibition of Vasopressin Induced Aggregation of Human Platelets

Human platelets endogenously express the V1a receptor. It was found thatrelatively high vasopressin concentrations (ca. 50-100 nM) stimulateplatelet aggregation ex vivo. Therefore, platelets enriched from humanblood may serve as a V1a expressing tissue for pharmacological studieswith corresponding high concentrations of vasopressin antagonists.

Human blood is collected in a 10 mM trisodium citrate solution by venouspuncture from nonsmoking healthy volunteers (n=4-8) who were drug freefor at least 1 week. Platelet-rich plasma (PRP) is obtained bycentrifuging the blood sample at 140 g for 20 min at 4° C. The resultingpellet is further centrifuged (15.000 rpm, 2 min) to produceplatelet-poor plasma (PPP). Platelet aggregation is measuredturbidimetrically using an aggregometer (APACT 4). The reaction isfollowed by monitoring changes in light transmission on 178 μL PRPaliquots, under continuous stirring at 37° C., against PPP control.Various concentrations of vasopressin antagonists (in 2 μL) are added toPRP 5 mM before the addition of 20 μL Arg-vasopressin (finalconcentration 100 nM. The inhibitory effects of the compounds aredetermined by measuring the height of the aggregation wave from thebottom of the shape change compared with the control response. IC50values are calculated a dose-response inhibition curve by an iterativenonlinear regression program

B-5. Effects on the Contraction of Isolated Rat Vessel Rings IsolatedAorta

Test compounds can be investigated on isolated aortic rings from maleWistar rats endogenously expressing the V1a receptor. Male Wistar ratsare euthanized using carbon dioxide. The aorta is removed and placed inice-cold Krebs-Henseleit buffer of following composition (in mmol/1):NaCl 112, KCl 5.9, CaCl₂ 2.0, MgCl₂ 1.2, NaH₂PO₄ 1.2, NaHCO₃ 25, glucose11.5. The aorta is cut into 3 mm rings and transferred to 20 ml organbaths containing Krebs-Henseleit solution equilibrated with 95% O₂, 5%CO₂ at 37° C. For recording of isometric tension the rings are mountedbetween two hooks. The resting tension is adjusted to 3 g. After anequilibration period, each experiment is started by exposing thepreparation to K+ (50 mM) Krebs-Henseleit solution. The aortic rings arethan pre-contracted using 1 nmol/1 Arg-vasopressin. After a stablecontraction is established, a cumulative dose response curve of the testcompound is constructed. The stabilized contraction induced byArg-vasopressin is defined as 100% tension. The relaxation is expressedas percentage tension.

Isolated A. Renalis

Male Wistar rats (200-250 g) are euthanized using carbon dioxide. The A.renalis is removed and placed in ice-cold Krebs-Henseleit buffer offollowing composition (in mmol/1): NaCl 112, KCl 5.9, CaCl₂ 2.0, MgCl₂1.2, NaH₂PO₄ 1.2, NaHCO₃ 25, glucose 11.5. For measurement of isometrictension, ring segments, 2 mm in length, are mounted in a small vesselchamber myograph (Danish Myo Technology A/S, Denmark) using two tungstenwires fixed to mounting jaws. One mounting jaw is attached to amicrometer, allowing control of vessel circumference. The other mountingjaw is attached to a force transducer for measurement of tensiondevelopment. The whole preparation is kept in a chamber withphysiological salt solution at 37° C., bubbled with oxygen. After a 30min equilibration period, the vessels are stretched to their optimallumen diameter for active tension development which is determined basedon the internal circumference-wall tension ratio. The internalcircumference is set to 90% of what the vessels would have if they areexposed to a passive tension equivalent to that produced by a transmuralpressure of 100 mmHg

Afterwards, the vessels are washed three times with Krebs-Henseleitbuffer and left to equilibrate for 30 min. The contractility is thentested by a twofold exposure to a high K⁺ solution (50 mmol/1 KCl).After washing with Krebs-Henseleit buffer the vessels are thenpre-contracted using 1 nmol/l Arg-vasopressin. After a stablecontraction is established, a cumulative dose response curve of the testcompound is constructed. The stabilized contraction induced byArg-vasopressin is defined as 100% tension. The relaxation is expressedas percentage tension.

B-6. In Vivo Assay for Detecting Cardiovascular Effects: Blood PressureMeasurement in Anaesthetized Rats (Vasopressin ‘Challenge’ Model)

Male Sprague-Dawley rats (250-350 g body weight) are used underketamine/xylazine/pentobarbital injection anaesthesia. Polyethylenetubes (PE-50, Intramedic®), prefilled with heparin-containing (500IU/ml) isotonic sodium chloride solution, are introduced into thejugular vein and the femoral vein and then tied in. Arg-vasopressin(SIGMA) is injected via one venous access, with the aid of a syringe;the test substance is administered via the second venous access. Fordetermination of the systolic blood pressure, a pressure catheter(Millar SPR-320 2F) is tied into the carotid artery. The arterialcatheter is connected to a pressure transducer which feeds its signalsto a recording computer equipped with suitable recording software. In atypical experiment, the experimental animal is administered 3-4successive bolus injections at intervals of 10-15 min with a definedamount of Arg-vasopressin (30 ng/kg) in isotonic sodium chloridesolution. When the blood pressure has reached initial levels again, thetest substance is administered as a bolus, with subsequent continuousinfusion, in a suitable solvent. After this, at defined intervals (10-15min), the same amount of Arg-vasopressin as at the start is administeredagain. On the basis of the blood pressure values, a determination ismade of the extent to which the test substance counteracts thehypertensive effect of Arg-vasopressin. Control animals only receivesolvent instead of the test substance.

Following intravenous administration, the compounds of the invention, incomparison to the solvent controls, bring about an inhibition of theblood pressure increase caused by Arg-vasopressin.

B-7. In Vivo Assay for Detecting Cardiovascular Effects: DiuresisInvestigations in Conscious Rats Kept in Metabolism Cages

Wistar rats (220-450 g body weight) are kept with free access to feed(Altromin) and drinking water. During the experiment, the animals arekept with free access to drinking water for 4 to 8 or up to 24 hoursindividually in metabolism cages suitable for rats of this weight class(Tecniplast Deutschland GmbH, D-82383 Hohenpeißenberg). At the beginningof the experiment, the animals are administered the test substance in avolume of 1 to 3 ml/kg body weight of a suitable solvent by means ofgavage into the stomach. Control animals only receive solvent. Controlsand substance tests are carried out in parallel on the same day. Controlgroups and substance-dose groups each consist of 4 to 8 animals. Duringthe experiment, the urine excreted by the animals is collectedcontinuously in a receiver at the base of the cage. The volume of urineper time unit is determined separately for each animal, and theconcentration of urinary electrolytes is measured by standard methods offlame photometry. Before the beginning of the experiment, the bodyweight of the individual animals is determined.

B-8. In Vivo Assay for Detecting Protective Renal Effects: AcuteIschemia/Reperfusion Injury Model in Rodents

Laboratory bred male C57Bl/6J mice 6-8 weeks old are obtained fromTaconic Biosciences, male 6-8 weeks old Sprague Dawley® rat are obtainedfrom Charles River. Both rats and mice are maintained under standardlaboratory conditions, 12 hour light-dark cycles with access to normalchow and drinking water at libitum. For the ischemia reperfusion injurymodel a total of 10-12 rats or mice is used in each control andexperimental group.

Animals are anesthetized with continuous inhaled isoflurane. A rightnephrectomy is performed through a right flank incision 7 days beforethe ischemic procedures in the contralateral kidneys.

For renal ischemia a left flank incision is made. Renal vessels areexposed by dissection of the left renal pedicle. Non-traumatic vascularclamps are used to stop blood flow (artery and vein) during 45 min(rats) or 25 min (mice) of ischemia. Reperfusion is established byremoving the clamps. The abdominal wall (muscular layer and skin) isclosed with 5.0 polypropylene sutures. Temgesic® (Buprenorphin, 0.025mg/kg s.c.) is applied as an analgesic.

Urine of each animal is collected in metabolic cages over night beforesacrifice at 24 h post ischemia. Upon sacrifice, blood samples areobtained under terminal anesthesia. After centrifugation of the bloodsamples, serum is isolated. Both serum creatinine and serum urea aremeasured via clinical biochemistry analyzer (Pentra 400). For theassessment of serum and urinary kidney injury biomarkers (Neutrophilgelatinase-associated lipocalin [NGAL], kidney injury molecule-1 [KIM-1]and Osteopontin) ELISA's are performed according to the manufacturersprotocol. Both urinary creatinine and albumin are measured to determinethe albumin/creatinine ratio.

Total RNA is isolated from kidneys. Left kidneys are snap-frozen inliquid nitrogen at sacrifice. Kidney tissue is then homogenized and RNAis obtained. Total RNA is transcribed to cDNA. Using TaqMan real-timePCR renal NGAL, Osteopontin, KIM-1, Nephrin and Podocin mRNA expressionis analyzed in whole kidney tissue.

Differences between groups are analyzed by one-way ANOVA with Dunnett'scorrections for multiple comparisons. Statistical significance isdefined as p<0.05. All statistical analyses are done using GraphPadPrism 6.

B-9. In Vivo Assay for Detecting Cardiovascular Effects: HemodynamicInvestigations in Anaesthetized Dogs

Male beagle dogs (Beagle, Marshall BioResources, USA) with a weight ofbetween 10 and 15 kg are anesthetized with pentobarbital (30 mg/kg iv,Narcoren®, Merial, Germany) for the surgical interventions and thehemodynamic and functional investigation termini. Pancuroniumbromide(Pancuronium Inresa, Inresa, Germany, 2-4 mg/animal i.v.) servesadditionally as a muscle relaxant. The dogs are intubated and ventilatedwith an oxygen/ambient air mixture (30/70%), about 2.5-4 L/minVentilation takes place using a ventilator from GE Healthcare (Avance,Germany) and is monitored using a carbon dioxide analyzer (-DatexOhmeda). The anesthesia is maintained by continual infusion ofpentobarbital (50 μg/kg/min); fentanyl is used as an analgesic (10μg/kg/h).

In preparatory interventions, the dogs are fitted with a cardiacpacemaker. At start of experiment, a cardiac pacemaker from Biotronik(Logos®, Germany) is implanted into a subcutaneous skin pocket and iscontacted with the heart via a pacemaker electrode (Siello 560®,Biotronik, Germany) which is advanced through the external jugular vein,with illumination, into the right ventricle.

Thereafter accesses are removed and the dog wakes spontaneously from theanesthesia. After a further 7 days, the above-described pacemaker isactivated and the heart is stimulated at a frequency of 220 beats perminute.

The actual drug testing experiments take place 28 days after thebeginning of pacemaker stimulation, using the following instrumentation:

-   -   Introduction of a bladder catheter for bladder relief and for        measuring the flow of urine    -   Attachment of electrocardiography (ECG) leads to the extremities        for ECG measurement    -   Introduction of a sheath introducer filled with sodium chloride        solution into the femoral artery. This tube is connected to a        pressure sensor (Braun Melsungen, Melsungen, Germany) for        measuring the systemic blood pressure    -   Introduction of a Millar Tip catheter (type 350 PC, Millar        Instruments, Houston, USA) through a port secured in the carotid        artery, for measuring cardiac hemodynamics.    -   Introduction of a Swan-Ganz catheter (CCOmbo 7.5F, Edwards,        Irvine, USA) via the jugular vein into the pulmonary artery, for        measuring the cardiac output, oxygen saturation, pulmonary        arterial pressures and central venous pressure    -   Siting of a venous catheter in the cephalic vein, for infusing        pentobarbital, for liquid replacement and for blood sampling        (determination of the plasma levels of substance or other        clinical blood values)    -   Siting of a venous catheter in the saphenous vein, for infusing        fentanyl and for administration of substance    -   Infusion of vasopressin (Sigma) in increasing dosage, up to a        dose of 4 mU/kg/min. The pharmacological substances are then        tested with this dosage.

The primary signals are amplified if necessary (ACQ7700, Data SciencesInternational, USA or Edwards-Vigilance-Monitor, Edwards, Irvine, USA)and subsequently fed into the Ponemah system (Data SciencesInternational, USA) for evaluation. The signals are recordedcontinuously throughout the experimental period, and are furtherprocessed digitally by said software, and averaged over 30 seconds.

Although the invention has been disclosed with reference to specificembodiments, it is apparent that other embodiments and variations of theinvention may be devised by others skilled in the art without departingfrom the true spirit and scope of the invention. The claims are intendedto be construed to include all such embodiments and equivalentvariations.

C) Working Examples of Pharmaceutical Compositions

The substances according to the invention can be converted topharmaceutical preparations as follows:

Tablet: Composition:

100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50mg of maize starch, 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF,Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

Production:

The mixture of the compound of Example 1, lactose and starch isgranulated with a 5% strength solution (m/m) of the PVP in water. Afterdrying, the granules are mixed with the magnesium stearate for 5 min.This mixture is compressed in a conventional tabletting press (see abovefor format of the tablet).

Oral Suspension: Composition:

1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mgof Rhodigel (xanthan gum) (from FMC, USA) and 99 g of water.

10 ml of oral suspension correspond to a single dose of 100 mg of thecompound of the invention.

Production:

The Rhodigel is suspended in ethanol, and the compound of Example 1 isadded to the suspension. The water is added while stirring. The mixtureis stirred for about 6 h until swelling of the Rhodigel is complete.

Sterile i.v. Solution:

The compound according to the invention is dissolved at a concentrationbelow saturation solubility in a physiologically acceptable solvent (forexample isotonic sodium chloride solution, glucose solution 5% and/orPEG 400 solution 30%). The solution is sterilized by filtration andfilled into sterile and pyrogen-free injection containers.

1. A compound of general formula (I)

in which R¹ represents a trifluoromethyl group or represents a group ofthe formula —Y—R², wherein Y represents a group of the formula

in which #¹ represents the point of attachment to R², #² represents thepoint of attachment to the rest of the molecule, R² represents a groupselected from a hydrogen atom, (C₁-C₄)-alkyl, 5- or 6-memberedcycloalkyl, 5- or 6-membered oxaheterocycloalkyl, wherein any(C₁-C₄)-alkyl group and any 5- or 6-membered cycloalkyl group are eachoptionally substituted with a group selected from amino and hydroxy, Arrepresents a phenyl group or a 5- or 6-membered heteroaryl groupattached via a ring carbon atom having one or two ring heteroatomsselected from a nitrogen atom and a sulfur atom, wherein any phenylgroup and any 5- or 6-membered heteroaryl group are each optionallysubstituted, identically or differently, with one or two groups selectedfrom a halogen atom, nitro, cyano, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy,(C₁-C₄)-alkylsulfanyl, (C₁-C₄)-alkoxycarbonyl, aminocarbonyl and—S(═O)₂NH₂, wherein said (C₁-C₄)-alkyl group, said (C₁-C₄)-alkoxy groupand said (C₁-C₄)alkylsulfanyl group are each optionally substituted withup to three fluorine atoms, or a pharmaceutically acceptable salt,hydrate and/or solvate thereof.
 2. A compound of general formula (I)according to claim 1, wherein R¹ represents a trifluoromethyl group orrepresents a group of the formula —Y—R², wherein Y represents a group ofthe formula

in which #¹ represents the point of attachment to R², #² represents thepoint of attachment to the rest of the molecule, R² represents a groupselected from methyl, aminomethyl, 5-membered cycloalkyl and4-morpholinyl, wherein any 5-membered cycloalkyl group is optionallysubstituted with hydroxy, Ar represents a phenyl group or a pyridinegroup attached via a ring carbon atom, wherein any phenyl group anypyridine group is each optionally substituted with one or two groupsselected from a fluorine atom, a chlorine atom, (C₁-C₄)-alkyl,(C₁-C₄)-alkoxy, nitro, cyano, methylsulfanyl and —S(═O)₂NH₂, whereinsaid (C₁-C₄)-alkyl group and said (C₁-C₄)-alkoxy group are eachoptionally substituted with up to three fluorine atoms, or apharmaceutically acceptable salt, hydrate and/or solvate thereof.
 3. Acompound of general formula (I) according to claim 1, wherein R¹represents a group of the formula —Y—R², wherein Y represents a group ofthe formula

in which #¹ represents the point of attachment to R², #² represents thepoint of attachment to the rest of the molecule, R² represents a methylgroup Ar represents a group of the formula

in which #¹ represents the point of attachment to the nitrogen atom,R^(3A) represents a group selected from cyano and trifluoromethoxy,R^(3B) represents a group selected from a chlorine atom andtrifluoromethyl, or a pharmaceutically acceptable salt, hydrate and/orsolvate thereof.
 4. A compound of general formula (I) according to claim1, wherein R¹ represents a trifluoromethyl group or represents a groupof the formula —Y—R², wherein Y represents a group of the formula

in which #¹ represents the point of attachment to R², #² represents thepoint of attachment to the rest of the molecule, R² represents a methylgroup, Ar represents a group of the formula

in which #¹ represents the point of attachment to the nitrogen atom,R^(3C) represents a group selected from a fluorine atom and a chlorineatom, or a pharmaceutically acceptable salt, hydrate and/or solvatethereof.
 5. The compound of formula (I) according to claim 1, whereinthe compound is selected from the group consisting of5-(4-Chlorophenyl)-2-{[5-(1,1-difluoroethyl)-1-(2-methylphenyl)-1H-1,2,4-triazol-3yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;5-(4-Chlorophenyl)-2-({1-(2,6-dichlorophenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(difluoromethyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;5-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-(2-methylphenyl)-1H-1,2,4-triazol-3yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;5-(4-Chlorophenyl)-2-({1-(2,6-difluorophenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;5-(4-Chlorophenyl)-2-{[5-(1,1-difluoroethyl)-1-(2,6-difluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;5-(4-Chlorophenyl)-2-{[1-(2,6-dichlorophenyl)-5-(1,1-difluoroethyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;5-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-(2-methylphenyl)-1H-1,2,4-triazol-3yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;5-(4-Chlorophenyl)-2-({5-[1-fluoroethyl]-1-[2-(propan-2-yl)phenyl]-1H-1,2,4-triazol-3yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;5-(4-Chlorophenyl)-2-({5-(1,1-difluoroethyl)-1-[2-(propan-2-yl)phenyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;5-(4-Chlorophenyl)-2-({1-(2-ethylphenyl)-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;5-(4-Chlorophenyl)-2-{[5-(1,1-difluoroethyl)-1-(2-ethylphenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;5-(4-Chlorophenyl)-2-({1-[2-(difluoromethoxy)phenyl]-5-[1-fluoroethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;5-(4-Chlorophenyl)-2-{[5-(1,1-difluoroethyl)-1-(2,6-dimethylphenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;and5-(4-Chlorophenyl)-2-({5-(1,1-difluoroethyl)-1-[2-(methylsulfanyl)phenyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.6. A method of preparing a compound of general formula (I) according toclaim 1 said method comprising the step [A] of allowing an intermediatecompound of formula (II):

in which R⁴ represents a (C₁-C₄)-alkyl group, in particular a methylgroup, to react in a first step in the presence of an at leaststoichiometric amount of a base with a compound of general formula(III):

in which Y and R² are as defined for the compound of general formula (I)according to claim 1, to give an intermediate compound, which is thenallowed to react in a second step with a hydrazie compound of generalformula (IV) or a respective salt thereof

in which Ar is as defined for the compound of general formula (I)according to claim 1, thereby giving a compound of general formula(I-A):

in which Y and R² are as defined for the compound of general formula (I)according to claim 1, or [B] of allowing an intermediate compound offormula (V):

to react with a compound of general formula (VI):

in which R¹ and Ar are as defined for the compound of general formula(I) according to claim 1, thereby giving a compound of general formula(I):

in which R¹ and Ar are as defined for the compound of general formula(I) according to claim 1, each [A] and [B] optionally followed, whereappropriate, by (i) separating the compounds of formula (I) thusobtained into their respective diastereomers, and/or (ii) converting thecompounds of formula (I) into their respective hydrates, solvates, saltsand/or hydrates or solvates of the salts by treatment with thecorresponding solvents and/or acids or bases.
 7. A compound of claim 1for the treatment and/or prevention of diseases.
 8. A medicamentcomprising a compound of claim 1 for the treatment and/or prevention ofa disease selected from the group consisting of acute kidney disease,chronic kidney disease, diabetic nephropathy, acute heart failure,chronic heart failure, preeclampsia, peripheral arterial disease (PAD),coronary microvascular dysfunction (CMD), Raynaud's syndrome,dysmenorrhea, cardiorenal syndrome, hypervolemic hyponatremia, euvolemichyponatremia, liver cirrhosis, ascites, edema, and the syndrome ofinadequate ADH secretion (SIADH).
 9. A method for the manufacture of apharmaceutical composition for the treatment and/or prevention of adisease selected from the group consisting of acute kidney disease,chronic kidney disease, diabetic nephropathy, acute heart failure,chronic heart failure, peripheral arterial disease (PAD), coronarymicrovascular dysfunction (CMD), Raynaud's syndrome, dysmenorrhea,cardiorenal syndrome, hypervolemic hyponatremia, euvolemic hyponatremia,liver cirrhosis, ascites, edema, and the syndrome of inadequate ADHsecretion (SIADH), the method comprising the step of manufacturing thepharmaceutical composition with a compound of claim
 1. 10. Apharmaceutical composition comprising a compound as defined in claim 1and one or more pharmaceutically acceptable excipients.
 11. Thepharmaceutical composition of claim 10, and one or more further activeingredients.
 12. The pharmaceutical composition as defined in claim 10for the treatment and/or prevention of a disease selected from the groupconsisting of acute kidney disease, chronic kidney disease, diabeticnephropathy, acute heart failure, chronic heart failure, peripheralarterial disease (PAD), coronary microvascular dysfunction (CMD),Raynaud's syndrome, dysmenorrhea, cardiorenal syndrome, hypervolemichyponatremia, euvolemic hyponatremia, liver cirrhosis, ascites, edema,and the syndrome of inadequate ADH secretion (SIADH).
 13. Method for thetreatment and/or prevention of a disease selected from the groupconsisting of acute kidney disease, chronic kidney disease, diabeticnephropathy, acute heart failure, chronic heart failure, preeclampsia,peripheral arterial disease (PAD), coronary microvascular dysfunction(CMD), Raynaud's syndrome, dysmenorrhea, cardiorenal syndrome,hypervolemic hyponatremia, euvolemic hyponatremia, liver cirrhosis,ascites, edema, and the syndrome of inadequate ADH secretion (SIADH), ina human or other mammal, comprising administering to a human or othermammal in need thereof a therapeutically effective amount of one or morecompounds as defined claim
 1. 14. Method for the treatment and/orprevention of a disease selected from the group consisting of acutekidney disease, chronic kidney disease, diabetic nephropathy, acuteheart failure, chronic heart failure, preeclampsia, peripheral arterialdisease (PAD), coronary microvascular dysfunction (CMD), Raynaud'ssyndrome, dysmenorrhea, cardiorenal syndrome, hypervolemic hyponatremia,euvolemic hyponatremia, liver cirrhosis, ascites, edema, and thesyndrome of inadequate ADH secretion (SIADH), in a human or othermammal, comprising administering to a human or other mammal in needthereof a therapeutically effective amount of a pharmaceuticalcomposition as defined claim
 10. 15. Pharmaceutical composition of claim11 wherein the one or more further active ingredients is selected fromthe group consisting of diuretic, angiotensin AII antagonist, ACEinhibitor, beta-receptor blocker, mineralocorticoid receptor antagonist,organic nitrates, NO donors, activators of a soluble guanylate cyclase,stimulators of a soluble guanylate cyclase, positive-inotropic agent,antiinflammatory agents, immunosuppressive agents, phosphate bindersand/or compounds which modulate vitamin D metabolism.